COVID-19 signalome: Pathways for SARS-CoV-2 infection and impact on COVID-19 associated comorbidity.

Introduction

SARS-CoV-2 (severe acute respiratory syndrome-coronavirus-2) is a highly transmissible and lethal coronavirus that first surfaced late in 2019. It sparked the pandemic of coronavirus disease 2019 (COVID-19), an acute respiratory disease that presents a threat to worldwide public health. Since 2019, the COVID-19 pandemic has been in the spotlight for intensive research to identify signaling pathways for SARS-CoV-2 infection and understand the impact of COVID-19 associated comorbidity [ 1 ].

Signalosomes as an example of molecular self-assembly and self-organization are a large supramolecular protein complex that can cluster or oligomerize and play a role in infectivity or serve as a therapeutic target. The COVID-19 signalosome is critical for both the understanding of infection and immune evasion. SARS-CoV-2 shares many characteristics with other coronaviruses, primarily in terms of genome composition, protein structure, and intracellular processes, which can result in moderate (or even asymptomatic) to severe infectious diseases. Although the mechanisms governing COVID-19 development are not completely understood, recent research suggests that SARS-CoV-2 behaves similarly to other coronaviruses. Uncovering the signaling pathways that may be altered by SARS-CoV-2 infection at the molecular and cellular levels is critical for a better understanding of the genesis and infection of SARS-CoV-2 [ 2 ]. This would include cellular interaction by angiotensin-converting enzyme 2 (ACE2) [ [3] , [4] , [5] , [6] , [7] , [8] ] and cytokine storm [ [9] , [10] , [11] ]. Moreover, it has been reported that SARS-CoV-2 triggers Golgi fragmentation via downregulation of the Golgi reassembly-stacking protein of 55 kD (GRASP55) to facilitate viral trafficking [ 12 ]. On the other hand, given the importance of the Raf/MEK/ERK signaling pathway in the pathogenesis of numerous viruses, it is likely that stimulation of this pathway by SARS-CoV-2 plays a key role in virus survival. Inhibitors of the Raf/MEK/ERK signaling cascade might be promising antiviral targets for the treatment of COVID-19 [ 13 ].

Several studies have looked at lipidomic profiling in COVID-19 patients. Although the analytical methodologies utilized and patient demographics vary among these studies, certain similar findings have been reported, notably with regards to blood cholesterol and lipoproteins. In individuals with COVID-19, serum triglycerides and very-low-density lipoprotein (VLDL) levels are much higher, although high-density lipoprotein (HDL) and low-density lipoprotein (LDL) levels remain significantly lower compared to age- and sex-matched healthy controls [ [14] , [15] , [16] , [17] ]. Comparison of COVID-19 patients to healthy controls by metabolomic and transcriptome profiling showed a change in fatty acid oxidation, which might imply a metabolic transition to feed viral replication [ 14 , 18 ]. Most studies have shown that following recovery, HDL and LDL levels reverted to baseline. However, other research suggested that changes in lipid metabolism continue even after COVID-19 recovery [ 19 , 20 ].

Given the presence of ACE2 in lungs, intestines, cardiovascular tissues, brain, kidneys, liver, and eyes, SARS-CoV-2 may have targeted these organs to further activate intracellular signaling pathways that lead to cytokine release syndrome (CRS). As a result, COVID-19 patients have experienced symptoms linked to all these systems [ 3 , 21 ]. A coherent cellular and molecular route for SARS-CoV-2 infection has been presented with the goal of combining early results [ 22 ]. In this proposed pathway, SARS-CoV-2 membrane fusion and cytoplasmic entry via ACE2 and transmembrane serine protease-2 (TMPRSS2)-expressing respiratory epithelial cells induce an initial immune response characterized by inflammatory cytokine production and a weak interferon response, particularly in interferon (IFN)-λ dependent epithelial defense [ 22 ]. However, as suggested by literature data, COVID-19 patients are characterized with heterogeneous patterns of IFN response. Jackson et al. [ 23 ] evaluated the expression levels of IFN in twenty-six critically ill SARS-CoV-2 patients treated with standard of care therapy. During the viral replication phase (day 8-10 of the infection), a peak in IFN-α2 expression was observed that decreased over time, but still remained at detectable levels. On the contrary, 19% of the patients were characterized with sustained abrogation of IFN-I production. Patients without IFN-α production had a poorer disease outcome requiring invasive ventilation. In the IFN-negative patient group, the viral load was higher, while IFN-β and -λ were also not detected. Controversial results of IFN response in COVID-19 patients suggest that patient screening for IFN production could be an important approach for therapeutic interventions of COVID-19 patients. Non-classic pathogenic T-cell differentiation and pro-inflammatory intermediate monocyte differentiation contribute to a skewed inflammatory profile, which is mediated by membrane-bound immune receptor subtypes (e.g., human immunoglobulin receptor II A (FcRIIA)) and downstream signaling pathways (e.g., nuclear factor-kappa B (NF-κB), p65 and p38 mitogen activated protein kinase (MAPK)), followed by chemotactic infiltration of monocyte-derived macrophages and neutrophils into lung tissue. Inflammatory cytokine release and delayed neutrophil apoptosis contribute to pulmonary thrombosis and cytokine storm. These mechanisms are consistent with clinical markers observed in COVID-19 patients, such as high tumor necrosis factor (TNF)-/IL-6 expression, elevated neutrophil-to-lymphocyte ratio (NLR), diffuse alveolar damage (DAD) via cell apoptosis in respiratory epithelia and vascular endothelia, elevated lactate dehydrogenase (LDH) and C-reactive protein (CRP), high production of neutrophil extracellular traps (NETs), low platelet count, and thrombosis [ 22 ]. Although key sections are likely to be updated as new discoveries emerge, the suggested pathways offer a number of possible treatment strategies. Additional therapies aim to reduce inflammatory signaling and damage, as well as to target molecular mediators of the maladaptive COVID-19 immune response (e.g., IL-6, TNF-, IL-17, JAK, and CDK9)[ 22 ].

It is widely known that pre-existing comorbid illnesses such as hypertension, diabetes, obesity, cardiovascular diseases (CVDs), chronic kidney diseases (CKDs), and chronic obstructive pulmonary disease (COPD) are linked to greater COVID-19 severity and mortality. The higher mortality from COVID-19 is attributable to the lack of a gold standard therapy and, more critically, not having a full understanding of how comorbid illnesses and COVID-19 interact at the molecular level, allowing tailored management methods to be implemented [ 24 ]. Barh et al. used multi-omics data sets and a bioinformatics approach to identify the pathway crosstalk between COVID-19 and diabetes, hypertension, CVDs, and CKDs [ 24 ]. On the other hand, limited evidence has shown that autoimmunity may be involved in patients with COVID-19 [ 25 ]. According to Sacchi et al., COVID-19 patients with a de novo autoimmune response had the poorest acute illness prognosis and outcome [ 25 ]. Their findings support the concept that SARS-CoV-2 infections are associated with autoimmune markers. However, research is still needed to define the pathway-pathway interaction in mental health and neurological and ophthalmic diseases.

Furthermore, SARS-CoV-2 signaling has been found to play a role in cell proliferation and death. The Coronavirus Research Group at the University of California isolated 26 SARS-CoV-2 proteins to create a network of virus-host protein-protein interactions [ 26 ]. They detected 332 human proteins targeted by SARS-CoV-2, as well as 69 FDA-approved drugs, which might be repurposed and evaluated in clinical trials for the disruption of the virus-host protein-protein interactions. Twenty-three of the 46 proteins evaluated in clinical trials on cancer were annotated [ 26 ]. Cancer cells and pathogens employ similar molecular pathways to control apoptosis and evade host defense. Infection with distinct RNA or DNA viruses has been associated with oncogenesis by activating cellular oncogenes or decreasing tumor suppressors, providing evidence for shared viral targets and cancer inducers [ 26 ]. As a result, system-wide integration of protein–protein interactions that drive viral pathogenicity and cancer has the potential to discover important factors that increase the dysregulation of cellular mechanisms [ 26 ].

In this review we present the importance of COVID-19 signalosome pathways in terms of infectivity, and pathway-pathway interactions. Moreover, we describe the impact of the COVID-19 signalome on COVID-19 associated comorbidity.

Pathways for systemic infection of SARS-CoV-2

ACE2-mediated infection

SARS-CoV-2 is mainly composed of four structural proteins, including spike glycoprotein (S), membrane (M), envelope (E) and nucleocapsid (N) proteins. Each protein has its distinct role in the viral replication process [ 27 ]. Additionally, SARS-CoV-2 presents biological features that are mainly involved in the interaction with ACE2 [ 2 ], which is widely expressed in the human body, including renal, lymphoid and cardiovascular tissues as well as the gastrointestinal (duodenum, jejunum, ileum, cecum and colon), respiratory and central nervous systems [ 3 ]. Based on different studies, it has been confirmed that ACE2 serves as a functional receptor for SARS-CoV-2 [ 2 ] ( Fig. 1 ). The cellular entry of SARS-CoV-2 is mediated by high affinity binding of the S protein to ACE2 and the processing of TMPRSS2 on the host cell surface allowing S protein priming [ 28 ]. Fig. 1 Overview of the SARS-CoV-2 infection mechanism and the post-infection host immune responses. The diagram illustrates the role of TMPRSS2, ACE-2, and CD147 during SARS CoV-2 infection, innate and adaptive immunity, and SARS-CoV-2 viral entry via receptors. Host immune defense begins early with the initiation of PRR signaling (TLRs, RLRs, CLRs and cGAS-STING) leading to activation of type I IFN along with proinflammatory cytokines [ 29 ]. The figure has been created using BioRender ( www.biorender.com ) Fig. 1

ER- and Golgi-mediated trafficking

SARS-CoV-2 can hijack coatomer protein-I (COPI) for S protein retrograde trafficking to the endoplasmic reticulum-Golgi intermediate compartment (ERGIC) [ 30 ]. The ERGIC acts as the progeny assembly site. In infected cells, the newly synthesized S protein in endoplasmic reticulum (ER) is transported first to the Golgi body, and then from the Golgi body to the ERGIC compartment. The resulting retrograde trafficking of the post-translationally modified S protein from the Golgi body to the ERGIC may include a cytosolic dibasic motif, Lys-x-His, where x is any amino acid [ 30 ]. Such C-terminal dibasic motifs and variants such as K-x-K-x-x are widely reported in the cytosolic tail of host membrane proteins. That is why the β-coronavirus S protein demonstrates molecular mimicry of dibasic trafficking motifs [ 30 ].

SARS-CoV-2 survival pathways

The Rapidly Accelerated Fibrosarcoma / Mitogen-activated protein kinase / Extracellular signal-regulated kinase (Raf/MEK/ERK) signaling pathway is one of the most well-known signal transduction pathways [ 31 ]. It shows an important impact on a wide variety of cellular functions such as cell proliferation, cell cycle arrest, and apoptosis. A chain of proteins in the cell transmits the signal from a surface cell receptor to the cellular DNA [ 31 ]. Previously, related to the SARS epidemic caused by SARS-CoV, it was demonstrated that the transiently expressed SARS-CoV S protein played an important role in virus-stimulated cyclooxygenase-2 (COX-2) expression [ 13 ]. COX-2 is a prostaglandin synthetase involved in inflammation, which is highly regulated by different factors, including cytokines. It has been shown that the SARS-CoV S protein induces calcium-dependent protein kinase C Alpha (PKCa) upstream, which in turn modulates the downstream Raf/MEK/ERK pathway [ 13 ]. A possible role of the Raf/MEK/ERK pathway in viral survival has been recently suggested for SARS-CoV-2 [ 13 ].

Immune escape pathways

The antiviral IFN system acts as the first line of defense against viral replication and dissemination. Surprisingly, IFN responses appear to be weak during the SARS-CoV-2 infection [ 32 ], indicating that the antiviral system is effectively counteracted by SARS-CoV-2 [ 33 ]. COVID-19 pathophysiology and severity are likely exacerbated by a lack of IFN responses, which allows productive viral replication [ [33] , [34] , [35] ].

The antiviral IFN system based on type I IFNs (particularly IFN-α and IFN-β) and type III IFNs (IFN-λ) plays an important role in host defense against viral infections [ [36] , [37] ]. Minimal production of antiviral IFNs in cultured cells, animal models, and in patients with severe COVID-19 clearly demonstrate the extremely effective suppression of innate immune responses by the virus [ [33] , [38] ]. Given the potent, diverse antiviral and immunoregulatory activities of type I and III IFNs, SARS-CoV-2 inhibition of IFN responses would not only directly facilitate the evasion of multifaced antiviral actions of numerous interferon-stimulated genes (ISGs) but affect numerous innate and adaptive immune responses. For example, natural killer (NK) cells, dendritic cells (DCs), macrophages, and lymphocytes contribute to cell-mediated release and clearance of viruses [ [39] , [40] , [41] ].

SARS-CoV-2 appears to be equipped with various IFN antagonists to interfere at multiple levels of the host antiviral IFN responses, which may contribute to its strong adaptation in the human population as demonstrated during the pandemic [ 42 ]. A number of putative IFN antagonists have been proposed since the beginning of the pandemic, each with a different mode of action. However, further studies are required to offer a clearer picture of the antagonism between SARS-CoV-2 and IFNs [ 42 ].

Cytokine storm

Induction of inflammatory cytokines by the SARS-CoV-2 S- protein, which is associated with epithelial damage and organ injuries may contribute to the cytokine storm in COVID-19 patients. The SARS-CoV-2 open reading frame 3a (ORF3a) also participates in induction of the cytokine storm. However, when concentrations of T helper (Th)17 cells, perforins, and granulysin-expressing cluster of differentiation 8 T-cell (CD8 T) cells are enhanced, it will contribute to hyperinflammation. Moreover, host Th17 responses are major contributors to cytokine storms [ 43 ]. Animal studies have shown that TNF-α and IFN-γ together induce a SARS-CoV-2-like cytokine storm in mice. The induced storm can be reversed using PANoptosis inhibitors [ 43 ].

Membrane lipids in SARS-CoV-2 cell entrance and infectivity

The lipid composition of cell membranes plays a role in viral cell entry, which can be attained by mediating fusion or affecting receptor conformation [ 44 ]. Several classes of lipid mediators can regulate the host immune response to viral infection. Examples of such mediators include eicosanoids and sphingolipids [ 44 ]. It has also been reported that the SARS-CoV-2 S protein can bind cholesterol in HDL particles, and that uptake of HDL by scavenger receptor class B type 1 (SR-B1) can occur. It can facilitate viral entry into cells, which co-express the ACE2 receptor [ 44 ].

The S protein in the envelope of SARS-CoV-2, responsible for binding and fusion to host cell membranes, is subjected to lipid modifications through the sequential action of zinc finger DHHC-type palmitoyltransferase 20 (ZDHHC20) and 9 S-acyltransferases [ 45 ]. Acetylation increases fusion capacity of viral particles and improves viral infectivity [ 46 ].

Sharing pathways with other viruses, bacteria, and protozoan parasites

Previous experimental and observational studies on inter-human viral infection have indicated a significant role of aerosols in the infection of many respiratory viruses, including influenza virus, SARS-CoV, SARS-CoV-2, and Middle East respiratory syndrome coronavirus (MERS-CoV) [ 47 ]. The most common symptoms of COVID-19 are similar to those seen in the case of influenza virus infection, including shortness of breath, fever, and running nose, in addition to other symptoms like loss of taste and smell, nausea, vomiting, and diarrhea [ 48 ]. Furthermore, SARS-CoV-2 immunization has been demonstrated to generate heterologous immunity against bacterial peptides. These findings suggest a mechanism for heterologous T-cell immunity against common bacterial infections and SARS-CoV-2, which might explain the wide range of COVID-19 clinical outcomes from asymptomatic to severe forms [ 49 ]. In the case of protozoan parasites, SARS-CoV-2 has been shown to share pathways with organisms causing toxoplasmosis, leishmaniasis, and malaria [ 50 ].

Signaling pathways deregulated in host tissues and organs

Lung

It is widely recognized that COVID-19 development is driven by an inflammatory state produced by hyperactivation of the immune system [ 51 ]. As a result, illness severity in individuals is caused not only by the viral infection, but also by the diversity of the host's innate and adaptive immune responses, which can result in a broad range of clinical outcomes, from asymptomatic to severe disease, multiple organ failure, and death [ 51 ]. A combination of cytopathic impact, prolonged inflammation, and immune system activation causes lung tissue damage and dyspnea [ 21 ]. Fassan et al. examined transcriptome data from post-mortem lung tissues and discovered a highly disturbed inflammatory pathway [ 52 ]. Genes specifically activating endothelial cells and TNF-family signaling pathways were downregulated in samples from COVID-19 patients compared to controls [ 52 ]. ISGs, monocyte/macrophage activation-associated genes, the complement system, and Cathepsin C were all upregulated in specimens from COVID-19 patients [ 52 ]. High levels of IFN in patients with severe COVID-19 might theoretically increase inflammation and tissue damage [ [53] , [54] ]. Recent research discovered low CD169/Siglec1 and high CD163 expression in circulating monocytes in patients with severe COVID-19, where the early stages of COVID-19 were characterized by enrichment of CD169/Siglec1+ monocytes in the peripheral blood [ 55 ]. Local CD163+ monocyte enrichment is related to anti-inflammatory macrophage actions [ 56 ], whereas CD169/Siglec1+ monocyte abundance implies IFN1 pathway activation [ 57 ]. IFN1 was identified as the primary driver of the dysregulated inflammatory and immunological milieu found in the lungs of COVID-19 patients [ 54 ].

Heart

COVID-19 survivors have been reported to suffer late-onset cardiovascular sequelae, including myocarditis-like alterations revealed by cardiovascular magnetic resonance imaging [ [58] , [59] , [60] ]. The long-term consequences of COVID-19 myocarditis, as well as the processes and extent of cardiac injury are yet unknown [ [58] , [59] , [60] ]. Emerging data show that autophagy plays an important role in SARS-CoV-2 infections [ 61 ]. SARS-CoV-2 has been found to causally modulate cellular metabolism to reduce autophagy for support of replication and propagation, similar to MERS-CoV [ [61] , [62] ]. SARS-CoV-2 has been found to reduce autophagy by interacting with Beclin1 to suppress antiviral innate immunity and increase viral escape and replication [ 62 ]. Many human heart disorders, including ischemia-reperfusion damage, myocardial infarction, cardiac hypertrophy, and heart failure, have been associated with Beclin1 deregulation [ 63 ]. Survivin, the smallest member of the family of apoptosis inhibitors, has been demonstrated to interact with Beclin1 [ 64 ]. Survivin overexpression is associated with an increase in critical components of the autophagy process, particularly Beclin1 [ 65 ]. There is evidence of an association between IFN-γ and Beclin1 activation in vitro and in vivo [ 66 ]. Notably, IFN-γ has been identified as an independent risk factor for death in individuals with moderate to severe COVID-19. It has been demonstrated that IFN-γ is expressed at much higher levels in COVID-19 patients compared to controls, and that this expression increases over time in severely ill COVID-19 patients [ 67 ]. According to Mormille, SARS-CoV-2 causes IFN-γ upregulation, which enhances Beclin1 expression and improves SARS-CoV-2 cell entry and infectivity [ 68 ].

Kidney

A link between SARS-CoV-2 infection and acute kidney injury (AKI) has been documented in more than one-third of hospitalized COVID-19 patients [ 69 ]. According to both native and post-mortem renal investigations, acute tubular damage is the histological characteristic of COVID-19 kidney disease [ 70 ]. Alexander et al. discovered higher levels of apoptosis in the kidneys of COVID-19 and Sepsis-AKI (S-AKI) patients [ 71 ]. The observed upregulation of the ceramide pathway in the COVID-19 AKI cohort, together with the lower oxidative phosphorylation signals, suggest that ceramide-induced apoptosis via mitochondrial disruption may play a role in tubular cell death [ [72] , [73] ]. The increased ceramide pathway in COVID-19 AKI supports the involvement of lipid dysregulation in severe cases of COVID-19, as previously proposed. Necroptosis, an immunogenic cell death process that may destroy virus-infected cells as well as activate both innate and adaptive immune responses to limit viral replication, was likewise more severe in the kidneys of COVID-19 patients [ 74 ]. Furthermore, the molecular signs of inflammation and immunological activation detected in the kidneys of COVID-19 patients point to a systemic antiviral response characterized by macrophage and T-cell-rich inflammation and type II IFN production, as revealed by blood-based tests [ 75 ]. On the other hand, SARS-CoV-2 specific CD4+ T cells directed against the S protein have been detected in patients with severe COVID-19 and may account for the CD4+ T cells found in the tubulointerstitial compartment of the kidneys [ 76 ]. The molecular pathways studied at both the genomic and proteomic levels indicated that inflammation, like S-AKI, is the primary cause of the kidney damage found in COVID-19 patients [ 70 ].

Liver

Another SARS-CoV-2 receptor, neuropilin-1 (NRP-1) has recently been shown to be expressed on the surface of host cells during infection [ [77] , [78] ]. NRP-1 belongs to the NRP protein family, which also contains NRP-2. NRP-1 was originally discovered in the central nervous system but has since then been identified in numerous cell types in the heart, lung, pancreas, skeletal muscle, and liver. NRP-1 is found in liver-resident cells, particularly nonparenchymal cells such as sinusoidal endothelial cells (LSECs) and hepatic stellate cells (HSC). NRP-1 has recently been discovered as a receptor that facilitates SARS-CoV-2 infection [ 78 ]. It may alter the state of liver disease in COVID-19 patients since it is expressed in liver cells [ 78 ]. The durability and severity of COVID-19-induced liver damage appear to differ. In most cases, liver function quickly returns to normal following viral infection, but individuals with severe illness may suffer long-lasting hepatic damage [ [79] , [80] ]. According to this observation, increasing severity of COVID-19 disease is associated with decreased hepatic function [ [21] , [81] ]. Recently, microvesicular steatosis as well as lobular and portal activity were discovered in the post-mortem examination of a COVID-19 patient [ 82 ]. ACE2 expression in cholangiocytes has also been hypothesized as a potential cause of liver damage. NRP-1 expression in LSECs and HSCs may thereby increase liver damage caused by SARS-CoV-2 infection [ 83 ].

Brain

Critically ill COVID-19 patients show increased levels of pro-inflammatory mediators and cytokines, indicating a "cytokine storm syndrome" [ 84 ]. The NF-κB pathway is upregulated in the severe/critical pathogenesis of the COVID-19 phenotype [ 85 ]. The NF-κB complex is found in both neurons and glia cells, and it has been linked to neurodegenerative disorders [ [86] , [87] ]. The NF-κB signaling pathway is regarded as a proinflammatory route, owing to its influence on transcription of several genes implicated in inflammation [ 88 ]. Inhibition of the NF-κB pathway boosted survival rates in mice infected with SARS-CoV, indicating that activation of the NF-κB signaling system contributes significantly to the inflammation caused by SARS-CoV infection [ 89 ]. The SARS-CoV S protein stimulates the NF-κB pathway in infected mononuclear cells. The cytokine response triggered by Toll-like receptor (TLR) activation was suppressed by NF-κB inhibition via protein kinase C-dependent mechanism [ 90 ]. As a SARS-CoV-2 binding protein, ACE2 can convert Angiotensin II, which can then function as a proinflammatory cytokine via the angiotensin-1-receptor (AT1R). AT1R can activate the NF-κB pathway [ 91 ] culminating in the creation of epidermal growth factor receptor (EGFR) ligands and TNF-α, which further activates NF-κB and propagates a "cytokine storm" [ [84] , [85] ]. According to emerging evidence, SARS-CoV-2 causes a variety of unanticipated consequences on neurological function, resulting in symptoms such as headache, decreased consciousness, anosmia, dysgeusia, stroke, encephalopathy, myelitis, neuritic pain, myalgia, and rhabdomyolysis [ 92 ]. COVID-19 shares a neuropathogenesis profile with other viruses that can activate the NF-κB pathway, such as MERS-CoV, herpes viruses, varicella, and cytomegalovirus (CMV) [ 93 ].

Eye

SARS-CoV-2 enters host cells using ACE2 as a receptor. Wang et al. discovered Basigin (BSG), also known as CD147, as a novel receptor for SARS-CoV-2 entry into host cells [ 94 ]. Although the cysteine proteases cathepsin B and L (CTSB/CTSL) can also execute this role to a lesser extent, TMPRSS2 is a major participant in cleaving and activating the SARS-COV-2 S protein for viral entry [ 28 ]. Determination of which cell types are susceptible to SARS-CoV-2 infection can be carried out by analyzing the expression of the above-mentioned genes in different organs. Other mechanisms of infection in addition to respiratory droplets have emerged. One alternative is the ocular pathway, which was recently discovered [ [95] , [96] ]. It has been suggested that ACE2 and TMPRSS2 may play roles in SARS-CoV-2 entry in ocular cells, where tissues in the cornea also express ACE2 and superficial conjunctival cells co-express ACE2 and TMPRSS2 [ 96 ]. The presence of interferon receptors (IFNAR1 and IFNAR2) in corneal conjunctival and endothelial cells suggests a possible association between these cell types and infection. During SARS-CoV infection, the virus suppresses the expression of transcription factors IRF3 and IRF7, which are essential for IFN induction [ 97 ]. The model of infection of conjunctival cells by viruses such as SARS-CoV-2 has been postulated and interaction between conjunctival and endothelial cells has been observed by looking at the expression of interferon regulators (IRFs) and receptors. IRFs are activated after viral infections. These IRFs (IRF7, IRF3, DDX3, and RIOK3) exhibit high expression in conjunctival cells based on basal gene expression in non-infected corneal cells [ 98 ]. IFNs generated by infected cell types may interface with endothelial cell types that express IFNARs such as IFNAR1 and IFNAR2 after infection [ 98 ]. STAT2 and IRF9 are also expressed at high levels in endothelial cells, which may trigger the release of cytokines such as IL-6, as seen by the high level of IL-6 expression in endothelial cells [ 98 ]. It has been demonstrated that IL-6 activates STAT3 transcription factors and the NF-κB pathway [ 99 ]. ACE2, on the other hand, has been demonstrated to inhibit STAT3 expression during lung inflammation [ 98 ]. Conjunctival cells express TMPRSS2 and ACE2, indicating that conjunctival sacs might be the entrance site for SARS-COV-2. CTSB and CTSL, on the other hand, were expressed in ACE2+ corneal epithelial cell types, indicating that SARS-CoV-2 might infect a specific population of epithelial cells in the cornea. SRY-Box transcription factor 13 (SOX13) was shown to be one of the intriguing gene candidates among the genes that were strongly co-expressed with ACE2 and TMPRSS2 [ 98 ]. SOX13 target genes such as PR domain zinc finger protein 1 (PRDM1) and phospholipid scramblase 2 (PLSCR2), affects IFN signaling pathways and generates high expression of IL-6 in endothelial cell types, which was detected while examining the microenvironment of corneal cell types, representing one of the cytokines that is highly expressed in patients with severe COVID-19 [ 98 ].

Skin

SARS-CoV-2 infection has been associated with the activation of cutaneous and systemic immune responses in different skin manifestations [ 100 ]. The type I IFN family, which contains three secreted cytokines IFN-α, IFN-β, and IFN-γ, is a major component of the immune response to numerous infections including SARS-CoV-2. These type I IFNs are generated in response to viral nucleotide sensing via TLRs. Type I IFNs are released and detected by other cells in the tissue environment [ 100 ]. However, when type I IFNs are triggered improperly in response to self-antigens or nucleic acid accumulation, this same mechanism can contribute to the development of autoimmune illnesses [ 101 ]. IFN response if one of the important factors in COVID-19 management, where early type I IFN response in some patients results in infection control and mild disease course. Therefore, severe COVID-19 has been associated with low type I IFN levels in the blood as well as reduced white blood cell expression of type I IFN-stimulated genes [ 102 ]. One of the signs of effective IFN response in COVID-19 patients is observed through skin manifestation of so-called “COVID toes”. This appearance is histologically characterized with epidermis edema and lymphocyte infiltration in perivascular and perieccrine regions, followed by formation of microthrombi in the blood vessels. The acral areas appear with red-purple discoloration and blistering. Similar changes are also observed in autoimmune disorders, such as familiar chilblain lupus, an interferonopathy correlated to increased IFN type I production. Appearance of the mentioned skin manifestation in COVID-19 patients suggests the presence and secretion of type I IFN that indicates mild COVID-19 course and efficient SARS-CoV-2 clearance. Other studies have demonstrated that defects in the type I IFN pathway, whether caused by mutations or the production of autoantibodies, predispose individuals to severe COVID-19 [ 103 ]. Surprisingly, it was discovered that 135 (or 14.4%) of 937 patients with severe COVID-19 developed autoantibodies against type I IFN, compared to 0% of patients with moderate or asymptomatic COVID-19 and 0.3% of healthy controls [ 103 ]. As a result, it is possible that individuals with pre-existing autoantibodies are predisposed to acquiring severe COVID-19. Fig. 2 schematically summarizes signaling pathways, which are deregulated in host tissues and organs and shows intricate complexity of the associated processes. Fig. 2 Summary of signaling pathways deregulated in host tissues and organs. The figure has been created using BioRender ( www.biorender.com ) Fig. 2

Pathway-pathway interactions in COVID-19 associated comorbidity and long-term consequences

Diabetes

Diabetes is considered an independent risk factor for COVID-19. Its macro- and microvascular complications affect the quality of life, and it is associated with several other infections. Many studies have demonstrated the high prevalence of diabetics who also suffered from COVID-19 [ [104] , [105] , [106] , [107] , [108] ]. According to an integrated analysis, people with severe COVID-19 show a severely compromised type I IFN response and low blood levels of IFN activity, which indicates a high blood viral load, and a compromised inflammatory response [ 38 ]. Additionally, it has been revealed that the TLR3 and IRF7 B cell immunity was associated with inborn errors in type I IFN immunity [ 35 ]. Furthermore, independent predictors of the severity of COVID-19 include blood levels of IL-6 and LDH [ 109 ]. In individuals with diabetes mellitus, the damage caused by IL-6 to DNA, proteins, lipids, and other components of the body might accelerate the progression of COVID-19. Pro-inflammatory cytokines with a Th1 cell signature are also known to worsen insulin resistance in obese people [ 110 ]. Acute respiratory viral infections have been demonstrated to enhance IFN production and to promote muscular insulin resistance in humans. This results in compensatory hyperinsulinemia, which maintains euglycemia and stimulates antiviral CD8+ T cell responses [ 111 ]. There is some evidence linking ACE2 to the control of hyperglycemia. For instance, it has been discovered that high-fat diets can cause pancreatic cell dysfunction, but ACE2-knockout animals are more vulnerable than wild-type mice to this condition. Additionally, SARS-CoV-2 infection can result in hyperglycemia in patients who do not already have diabetes mellitus [ [112] , [113] ].

Thrombosis and vascular injury

Abnormal clotting, thrombosis, microvascular lesions, and preeclampsia are clear complications that patients with COVID-19 are facing, leading to abnormal vascular problems [ 114 ]. Neutrophils are the main cell type recruited to the lungs during SARS-CoV-2 infection, which has been confirmed in several studies, demonstrating their association with thrombosis and microvascular injury [ 114 ]. There are a number of proinflammatory cytokines and chemokines that can be differently expressed in the cytokine-cytokine receptor and chemokine signaling pathways [ 115 ]. Down-regulated chemokine ligand 14 (CXCL14) promotes the ability of epithelial cells to produce chemokines, which will lead to additional neutrophil recruitment. Up-regulated CXCL1, CXCL2, CXLC3, CXCL5, and CXCL8 have a prominent role associated with the recruitment of neutrophils to the lungs [ 115 ]. Additionally, type I IFN responses are recognized to be essential for a coordinated and effective immune response to viral infections [ 116 ]. The only ISG that was up-regulated during the type I IFN response in lung epithelial cells infected with SARS-CoV-2 was IL-6 [ 115 ], which is similarly crucial for neutrophil recruitment, function, and survival. An increased number of neutrophils that generate superoxide at a higher rate than typical neutrophils as a result of IL-6 upregulation, may result in tissue damage [ 114 ]. Similarly, neutrophil extracellular trap (NET) formation has been shown to be crucial for the pathophysiology of pulmonary lung diseases like COPD or acute lung damage. Several important cytokines that are crucial for NET regulation and synthesis, such as CCL20, IL-6, TNF, CXCL8, and IL-1, were up-regulated [ [117] , [118] ]. Several studies have demonstrated that pulmonary microvascular thrombosis may be responsible for the high mortality rate in patients with SARS-CoV-2 and acute respiratory distress syndrome. There are reports that thrombosis is commonly found in small vessels, lungs and even some extrapulmonary organs [ [119] , [120] ]. Platelets are one of the key factors in thrombosis. It is interesting to note that in samples from COVID-19 patients, a considerable up-regulation of colony stimulating factor 2 (CSF2), CSF3, IL-6, and IL-1 occurred. These cytokines are known to play a role in platelet formation and megakaryocytic activity [ [121] , [122] , [123] ].

Hypertension and cardiovascular diseases

Hypertension has been reported in surveys in several countries as the most common comorbidity among individuals infected with SARS-CoV-2. Associated with heart failure and arrhythmia are some of the diseases of the cardiovascular system that can generate several complications in the course of SARS-CoV-2 infection [ [124] , [125] , [126] ]. Hypertension has been shown to be associated with a significantly higher risk of respiratory infection, making it a strong indicator of the severity of COVID-19. Hyperinflammation or "cytokine storms" are caused by SARS-CoV-2 infection, which stimulates both innate and adaptive immune responses and causes the production of proinflammatory substances. Type I IFN, which is essential for preventing viral infections, is decreased in patients with severe COVID-19 due to a large reduction in ISGs [ 38 ]. A decline in immune cells such as CD4+ T cells, CD8+ T cells, NK cells, and B cells induces lymphopenia [ 127 ]. IL-1, IL-6, IL-17, and TNF-α are among the cytokines with rapidly enhanced levels in the blood in the majority of individuals with severe COVID-19 resulting in "cytokine storm" [ 128 ]. Immune cells that produce cytokines contribute to organ damage and vascular dysfunction. In the inflammatory environment, patients with hypertension have higher levels of circulating monocytes, macrophages, CD8+ T cells, and CD4+ T cells [ 129 ]. High blood pressure causes immune cell infiltration and activation in the heart, as well as an immediate cardiac inflammatory response. Additionally, patients with catastrophic outcomes showed significant levels of CD38+ and human leukocyte antigen-DR isotype-positive (HLA-DR+), two essential indicators of CD8+ T-cell activation, as well as programmed cell death protein 1-positive (PD-1+), a hallmark of CD8+ T-cell activation and exhaustion, on CD8+ T cells after SARS-CoV-2 infection. Immunoglobulins like IgG, IgM and IgA as well as the proportions of SARS-CoV-2-specific IFN+ CD4+ T cells and IFN+ CD8+ cells were all significantly lower in fatal cases, indicating that T cells are crucial for clinical outcomes in COVID-19 patients with hypertension [ 130 ].

Renal diseases

The increase in the hospital mortality rate from COVID-19 is associated with kidney injuries in patients, because, just as the death of epithelial cells is induced by histones, the histones of NETs also induce the death of tubular epithelial cells, which leads to kidney injury [ 131 ]. In situ studies of the viral nucleocapsid protein in post-mortem kidneys demonstrated that SARS-CoV-2 antigens had accumulated in the renal tubules, suggesting that SARS-CoV-2 infects human kidneys directly, inducing AKI and contributing to viral spread in the body [ 132 ]. The production of a cytokine storm induces T cell necrosis or death, which results in a decrease in T cells, especially in situations of severe illness, lower levels of circulating CD4 and CD8 T cells, and higher levels of IL-10 and TNF [ 133 ]. Because macrophages are crucial, innate immune cells have the ability to detect infections, respond, and produce inflammatory chemicals to eliminate them and aid in tissue healing. SARS-CoV-2 enters macrophages, which then release IL-12 to further activate Th1 cells by presenting viral antigens to CD4+ and Th1 cells. B cells are stimulated to generate antigen-specific antibodies by the activated Th1 cells, and CD8+ and T-killer cells (CD8+ and Tk) are directed against cells carrying viral antigens [ 134 ]. CD8+ T cells have an antiviral function and either directly or indirectly cause their cytotoxic effect. T cells activate the NF-κB signaling pathway, which results in the generation of pro-inflammatory cytokines. Following the secretion of chemokines and cytokines such as IL-21, IL-8, TNF-α, IL-6, IL-1β, C-C motif chemokine ligand (CCL)-2, -3, and -5, the cytokine storm occurs, being responsible for multiple organ damage [ 135 ]. The cytokine storm may contribute to AKI in COVID-19 patients through interaction with renal resident cells. IL-6 causes renal endothelial cells to secrete pro-inflammatory chemokines and cytokines and increases kidney vascular permeability, which may lead to microcirculatory dysfunction [ 136 ]. On the other hand, viral infection causes CD4+ T cells and NK cells to infiltrate into the tubular interstitium and releases pro-inflammatory cytokines, which damages the tubules. If these immune cells are overactive after entering the infected kidney, it can cause fibrosis, apoptosis, and microvascular changes [ [137] , [138] ].

Neurological syndromes and mental health

It is evident that after infection by SARS-CoV-2 many patients present neurological symptoms and syndromes [ 139 ]. Persistence of multiple symptoms, particularly fatigue, dyspnea, sleep disturbances, and subjective memory complaints, has been reported [ 140 ]. The long-term consequences of COVID-19 involve the central and peripheral nervous systems [ [139] , [140] , [141] , [142] ]. The risk of cerebrovascular events (ischemic stroke and intracranial hemorrhage) is considered high for COVID-19 [ [143] , [144] ]. Multiple organ failure has been identified as the cause of a significant proportion of SARS and COVID-19 deaths. Through the stimulation of glial cells and the ensuing large production of inflammatory molecules including cytokines, chemokines, and other inflammatory signals, a neurotropic virus can induce persistent inflammation and brain injury [ 145 ]. The brain-blood barrier (BBB) is then significantly breached as a result of the inflammatory signals that are generated, which activates and amplifies the neuroinflammatory process [ 145 ]. It has been demonstrated that SARS-CoV infections cause primary glial cells to release interleukins, including IL-6, IL-12, IL-15, and TNF-α in vitro [ 146 ]. Additionally, it has been documented that IL-6 is positively correlated with the severity of COVID-19 symptoms [ 145 ].

Ophthalmic diseases

In a large series of cases with mild COVID-19, 11 out of 127 (8.66%) patients had conjunctivitis, which is the most common ophthalmic manifestation documented in patients with COVID-19 [ 147 ] Many of the characteristics that increase the chance of acquiring COVID-19 also enhance the risk of developing eye conditions including age-related macular degeneration (AMD). The impact of elevated levels of various pro-inflammatory cytokines, including IL-6 and TNF-α receptor 2, on the development of advanced stages of AMD has been investigated [ 148 ]. One prospective study of 251 participants aged 60 and older found that the highest quartile of CRP levels was associated with a relative risk of 2.10 (95% CI 1.04–41.18) and the highest quartile of IL-6 serum levels was associated with a relative risk of 1.81 (95% CI 0.97–3.36) for progression to advanced stages of AMD [ 148 ]. On the other hand, the pathophysiology of drusen and AMD is intricately linked to inflammation. A histologic study of drusen-covered eyes revealed the presence of macrophages in addition to complement deposits [ 149 ]. The production of several factors, including hypoxia-inducible factors (HIFs), is known to cause monocyte migration. HIF1 promotes the synthesis of several proangiogenic molecules, such as vascular endothelial growth factor-A (VEGF-A), as well as immune system modifiers including monocyte chemoattractant protein-1 (MCP-1) and TNF-α, each of which can draw myeloid cells to hypoxic regions. Fibrosis and blood vessel ingrowth are features of late AMD [ 149 ]. A range of cytokines, including IL-2, IFN-γ, and TNF-α, are secreted by M1 macrophages to support local immunity and their phagocytic activity. The development of blood vessels is supported by the so-called M2 macrophages, which are alternately activated. They release cytokines such as TGF-β and IL-10. M1 macrophages often decrease with age, but in contrast, M2 macrophages increase in older persons [ [150] , [151] ].

Cancers

Patients undergoing cancer treatment who have been diagnosed with COVID-19 generally possess factors associated with risk of death, which are similar to comorbid factors such as hypertension and cardiovascular diseases, advanced age, and male gender, as previously demonstrated [ 152 ]. In addition, patients who have received recent anti-tumor treatment may be at increased risk of severe COVID-19 [ [152] , [153] ]. According to some recently published studies, cancer patients are more vulnerable to the complications of COVID-19, but the susceptibility of cancer patients to SARS-CoV-2 infection has not yet been demonstrated [ [154] , [155] ]. Patients with COVID-19 were shown to have elevated levels of many cytokines during the early stages of the pandemic, including IL-6, IL-1, TNF-α, and IFNs [ 21 ]. IL-6, a proinflammatory cytokine with immunological functions, tissue regeneration, and metabolism, is a key player in this process despite the fact that more than 50 cytokines and growth factors have been linked to aberrant signaling reactions [ 155 ]. In this context, the JAK/STAT signaling pathway is considered one of the main potential pathways since IL-6 was also found to be abnormally hyperactivated in many different forms of cancer. In individuals with severe COVID-19, either CD4 lymphopenia-induced lymphocytic dysregulation or excessive production of proinflammatory cytokines downstream of IL-6 are responsible for immune dysregulation [ 156 ]. Patients with severe COVID-19 frequently have elevated levels of proinflammatory cytokines such as IL-2, IL-6, IL-7, IL-10, IFNs, and TNF-α [ 78 ]. Given that patients with severe COVID-19 and patients with disseminated malignancies both showed excessive plasma IL-6 levels, it is feasible that IL-6 or one of its downstream components may be an effective target for COVID-19 therapy.

Type I IFN possesses an essential additional signaling mechanism. Both immune responses against cancer and viral infections require type I IFN responses [ 157 ]. Impaired type I IFN signaling is linked to tumor development because IFN is essential for preventing tumor growth and inducing tumor cell senescence and death [ 158 ]. In response to SARS-CoV-2 infection, type I IFN signaling was shown to be suppressed [ 33 ]. Additionally, peripheral blood samples from patients with severe or critical COVID-19 showed low levels of type I IFN and ISGs as well as increase in IL-6 and inflammatory responses [ 38 ].

Immune checkpoint signaling is the third signaling pathway that is typical for cancers and COVID-19 [ 159 ]. It is an immunosuppressive pathway that involves the interaction of immune checkpoint molecules expressed in immune cells (especially T cells) with their corresponding ligands responding to pathogens or cancerogenic cells. First, the major histocompatibility complex (MHC) on antigen presenting cells (APCs) is recognized by T cell receptors (TCRs) on antigen-specific T cells. Then, CD28 on T cells must send signals to APCs carrying CD80/CD86. To reduce the hyperactivation and length of the immune responses, a number of immune checkpoint molecules (receptors) and their associated ligands interact [ 159 ]. PD1, programmed cell death 1 ligand 1 (PDL1, also known as B7-H1) and cytotoxic T lymphocyte antigen 4 (CTLA4)-CD80/CD86 are the receptor-ligand combinations that have been the subject of most research. The question of whether immune checkpoint inhibitor (ICI) treatment for cancer patients carries an increased risk during the COVID-19 pandemic is still up for debate. Cytokine storms during SARS-CoV-2 infection cause T-cell hyperactivation, which leads to fatigue and is linked to concomitant lymphopenia [ 160 ]. There are still some issues regarding the use of ICI to treat COVID-19. Through ICI, worn-out T cells may be reactivated and develop immunological competence. However, revitalized T cells may also boost cytokine production and raise the possibility of the cytokine storm, which might ultimately result in harmful lesions in various organs [ 161 ].

Autoimmune diseases

When the immune system does not recognize auto-components, it produces autoantibodies against the body's own cells, tissues, or organs, causing inflammation, which leads to autoimmune disease [ 162 ]. Regarding patients affected by SARS-CoV-2, its specific pathogenic mechanism of action is still not completely understood. However, there are reports in the literature of a patient who developed Systemic Lupus Erythematosus after infection with SARS-CoV-2 [ 163 ]. SARS-CoV-2 infections induce inflammatory cytokines, according to several studies [ 164 ]. Particularly, it has been suggested that this immune response might either assist in fighting viruses or increase the production of inflammatory chemokines, resulting in an "inflammatory storm" that could worsen the already serious conditions of patients [ 165 ]. The same process has been proven to cause familial chilblains and other autoimmune diseases like lupus for development of autoimmune diseases when type I IFNs are incorrectly activated in response to self-antigens or nucleic acid accumulation [ 101 ]. Low type I IFN blood levels and decreased type I ISG expression in white blood cells were linked to severe COVID-19 [ 102 ]. Therefore, it is probable that individuals with existing autoantibodies are more likely to develop severe COVID-19.

Fig. 3 summarizes these considerations by presenting pathway-pathway interactions in COVID-19-associated comorbidity and long-term consequences with the focus on different diseases. Fig. 3 Pathway-pathway interactions in COVID-19-associated comorbidity and long-term consequences with the focus on different diseases. The figure has been created using BioRender ( www.biorender.com ) Fig. 3

SARS-CoV-2 signaling in cell proliferation and apoptosis

Modulating oncogenic pathways and implementation

Viruses have found strategies to target and modify essential biochemical pathways with a small number of proteins in order to proliferate. To counteract immune responses, viruses can alter the cell cycle, attract host DNA-damage machinery to replication sites, hijack host translation machinery, reduce apoptosis by dampening signaling pathways, and reprogram host epigenetic markers [ [166] , [167] ]. To regulate apoptosis and elude host protection, cancer cells and pathogens use comparable molecular processes. Infection with specific RNA or DNA viruses has been associated with oncogenesis by activation of cellular oncogenes or inhibition of tumor suppressors. As a result, systemwide integration of protein–protein interactions that drive viral pathogenicity and cancer holds promise for identifying key factors that promote dysregulation of cellular mechanisms [ 26 ].

One of the hallmarks of cancer is dysregulation of cell-cycle control, since cancer cells continue to proliferate despite changes in pathways that provide continuous growth signals and permit evasion of cell-cycle arrest and apoptosis. Because viruses rely on their capacity to multiply in host cells to survive, it is no surprise that they disrupt the host cell cycle. Viruses can either terminate or accelerate cell division. A number of proteins associated with cell-cycle progression in the SARS-CoV-2 interactome has been identified, including proteins associated with the centrosome, mitotic spindle, and cytokinesis control [ 168 ]. Chemoinformatic analysis suggested that some anticancer drugs that have previously been licensed or are in clinical development can be effective against these proteins. Dabrafenib, a drug used to treat B-Raf Proto-Oncogene, Serine/Threonine Kinase (BRAF)-related malignancies, is thought to inhibit NIMA related protein kinase 9 (NEK9), a protein that interacts with SARS-CoV-2 NSP9. Furthermore, ponatinib and pazopanib are expected to suppress the activity of receptor-interacting serine/threonine protein kinase 1 (RIPK1), a SARS-CoV-2 NSP12 interactor linked to apoptosis, necroptosis, and inflammatory processes [ 168 ]. The avian coronavirus infectious bronchitis virus (IBV) has previously been demonstrated to cause cell-cycle arrest and replication stress by activating ATR-dependent DNA damage repair mechanisms [ 169 ]. Furthermore, ATR signaling inhibitors inhibited IBV replication. Replication stress activates the DNA damage signaling pathway, which is similar to the oncogene-induced phenomena seen in cancer cells. ATR-mediated signaling is increased in cancer cells with a faulty G1 checkpoint caused by mutation of TP53 or loss of RB1. Similarly, SARS-CoV causes cell-cycle arrest in the G1 phase via the retinoblastoma pathway, implying that ATR inhibitors might be used to treat COVID-19 [ 170 ].

Several SARS-CoV-2 viral proteins have been identified to interact with metabolic proteins [ 26 ]. Complex I interactions are particularly intriguing because metformin is known to inhibit this complex. Metformin treatment of SARS-CoV-2-infected cells led to a small reduction in viral load, suggesting that SARS-CoV-2 hijacks this complex for reproduction [ 168 ]. ETC is a generator of reactive oxygen species (ROS), and oxidative stress and ROS have a role in viral infection pathogenesis. Interactions with this pathway have been discovered, such as between ORF3a and heme oxygenase 1 (HMOX1), as well as NSP14 and sirtuin 5 (SIRT5) [ 171 ]. NFE2-like bZIP transcription factor 2 (NFE2L2) interacts with the promoter of HMOX1 and promotes its expression. Under oxidative stress, the activity of NFE2L2 is controlled by Kelch-like ECH-associated protein 1 (KEAP1). Both NFE2L2 and KEAP1 are often mutated in lung cancer patients, emphasizing the pathway's relevance in tumor development [ 171 ]. SIRT5, an NSP14 interactor, has been found to control NFE2L2 transcriptionally, and increased SIRT5 levels in lung cancer contributing to tumor growth and treatment resistance [ 172 ]. SARS-CoV-2 might leverage these connections to disrupt essential mechanisms governing mitochondrial metabolism and oxidative stress, including pathways known to be important in tumor growth [ 26 ].

Viruses have developed mechanisms to modify the host epigenome in order to counteract host immune responses for efficient viral replication. Both viral infections and cancer growth have been linked to epigenetic alterations caused by histone methyltransferases and deacetylases [ 173 ]. The histone methyltransferase NSD2 interacts with NSP8, while the histone deacetylase HDAC2 interacts with NSP5. NSD2 and HDAC2 are linked via many carcinogenic mechanisms. NSD2 catalyzes the monomethylation and dimethylation of histone H3 Lys36 (H3K36), and enhanced NSD2 catalytic activity causes transcriptional alterations seen in cancers such as multiple myeloma, acute lymphoblastic leukemia, and solid tumors [ 174 ]. NSD2 also interacts with bromodomain-containing protein 4 (BRD4), a protein from the bromodomain and extra-terminal (BET) family. The SARS-CoV-2 E protein has been shown to interact with BRD4 and BRD2. BET proteins are highly conserved epigenetic readers and transcriptional regulators that are attracted to super enhancers in the chromatin, and hence play a role in antiviral signaling as well as modulating virus-induced inflammation [ 175 ]. BRD4 and BRD2 are human immunodeficiency virus (HIV) transcription suppressors in latently infected cells. As a result, BET protein inhibitors have been found to reverse HIV latency in cell lines and several primary cell models. A possible scenario for the interaction of SARS-CoV-2 E protein with host BET proteins suggests that the virus suppresses the activity of these proteins by sequestering them out of the nucleus. BET inhibitors may work as antiviral drugs by disrupting the interaction of the E protein with BET proteins. BET inhibitors exhibited either little or no impact on viral infection in SARS-CoV-2-infected cells in vitro , indicating that additional mechanistic research is needed [ 168 ]. Epigenetic alterations are widespread in cancer and can have a significant impact on the transcriptional landscape of the cell. Understanding the mechanisms behind these alterations might speed up the repurposing of anticancer medications for COVID-19 therapy [ 26 ].

Viruses continue to develop new ways to capture and hijack the cellular translation machinery. The SARS-CoV NSP1 protein is known to bind to 40S ribosomes and preferentially promote endonucleolytic cleavage of host mRNAs [ 176 ]. One of these, La ribonucleoprotein 1 (LARP1), acts as a phosphorylation-sensitive switch that controls whether a collection of mRNAs with a 5′ terminal oligopyrimidine (TOP) motif are repressed or activated during translation [ 177 ]. LARP1 has been shown to promote carcinogenesis in malignancies, particularly those associated with viral infections and in the context of cancer, mammalian target of rapamycin (mTOR) signaling is one of the interactors and regulators of LARP1 [ 177 ]. A set of substrates, including LARP1, bind to eukaryotic initiation factor 4 E (eIF4E) and control TOP mRNA translation. Rapamycin is an FDA-approved drug that prevents LARP1 from binding to mTORC1 and is already being used to treat a variety of malignancies. Sapanisertib, a small molecule mTOR inhibitor, is now being studied in clinical trials for breast cancer, lung cancer, and other advanced solid tumors. In vitro, neither of them showed antiviral efficacy as monotherapeutic drugs [ 168 ]. However, zotatifin, an inhibitor of host mRNA translation, inhibited SARS-CoV-2 infection in in vitro models, indicating that viral replication is dependent on host mRNA translation [ 168 ]. Additionally, zotatifin and tomivosertib are now in clinical development for solid tumors.

Centrosome-associated proteins, nuclear pore proteins, ER quality control proteins, RNA processing proteins, respiratory electron transport proteins, and Ras-associated binding (RAB) signaling proteins have been identified as key targets of SARS-CoV-2 [ 26 ]. The enormous number of drugs which have been used for the treatment of diverse cancer types opens up the possibility of therapeutic repurposing. For example, cancer medications like midostaurin and ruxolitinib are also potential inhibitors of human proteins targeted by SARS-CoV-2. They target microtubule affinity regulating kinase (MARK) -2 and -3, which are important in controlling microtubule stability and cell polarity. The transporter protein ATP-binding cassette subfamily C member 1 (ABCC1) is targeted by daunorubicin and verapamil, both of which boosted SARS-CoV-2 infection in vitro. Multiple cancer therapies are being tested using pevonedistat, a c-Cbl conjugates neural precursor cell-expressed, developmentally downregulated 8 (NEDD8) inhibitor. Silmitasertib inhibits casein kinase 2 alpha 2 (CSNK2A2), a serine/threonine protein kinase involved in stress granule modulation [ 26 ].

SARS-CoV-2 modulated apoptosis and its implementation

Cell death pathways have been postulated to play an important role in SARS-CoV-2 infection [ 178 ]. Programmed cell death can be subverted by viruses. Furthermore, viruses can evade the host immune response. Programmed cell death and inflammation are mainly controlled by proteins of the death domain (DD) superfamily, which comprises the DD, death effector domain (DED), caspase activation recruitment domain (CARD), and pyrin domain (PYD) subfamilies [ 179 ]. Thus, the target of the DD proteins of the extrinsic pathway could play an essential role in viral infections regarding inflammation control and be capable of restoring the innate immune response. The extrinsic cell death pathway is triggered through death receptors (DRs) [ 180 ]. The key signaling platforms involved in induction of cell death through CD95 and DR4/5 and SARS/SARS-CoV-2 infection, as well as their cross talk are illustrated in Fig. 4 . Fig. 4 Overview of SARS-CoV-2 signaling in cell proliferation and apoptosis. The figure has been created using BioRender ( www.biorender.com ) Fig. 4

A recent study has demonstrated that the ORF3a protein of SARS-CoV-2, a key accessory protein, induces apoptosis in cells. Thus, these findings extend our knowledge of ORF3a, which will probably help to shed light on the pathogenicity of SARS-CoV-2 [ 181 ].

Conclusion

The COVID-19 signalome presents a significant impact on pathways associated with SARS-CoV-2 infection, the deregulation of pathways in tissues and organs of infected individuals, and pathways affecting comorbidity and long-term consequences of COVID-19. In this review, we have tried to dissect the relevant signaling pathways. In the case of SARS-CoV-2 infection, it has been well documented that its infection is mediated by ACE2, the functional receptor for SARS-CoV-2 and other coronaviruses. It has also been established that SARS-CoV-2 can hijack the cellular COP1 protein for retrograde trafficking of its S protein through the ER and Golgi compartments. Related to the Raf/MEK/ERK pathway, it was demonstrated that the SARS-CoV S protein stimulated COX2 expression, suggesting a possible role for Raf/MEK/ERK in SARS-CoV-2 survival also providing a potential therapeutic strategy against COVID-19. In the context of immune escape pathways, it has been shown that SARS-CoV-2 can efficiently counteract host antiviral systems. For example, IFN response inhibition by SARS-CoV-2 not only prevents antiviral actions of ISGs, but also affects innate and adaptive immune responses. However, some controversy has been described for IFN in relation to SARS-CoV-2 infections [ 102 ]. In this context, SARS-CoV-2 can induce overt but delayed type I IFN responses, whereas for example SARS-CoV-2 ORF6 seems to inhibit IFN production [ 33 ]. Moreover, imbalanced inflammatory responses against SARS-CoV-2 can lead to low levels of type I and III IFN production [ 34 ] and increased COVID-19 pathology [ 35 ]. Additionally, analysis of the kinetics of IFN plasma levels in COVID-19 patients demonstrated peak levels of IFN at day 8-10 of COVID-19 symptom onset [ 102 ]. Generally, IFN levels decreased with time. However, some patients showed no IFN expression indicating a poorer outcome.

Moreover, SARS-CoV-2 infections have been characterized by the induction of inflammation leading to epithelial damage and organ injuries contributing to cytokine storms. SARS-CoV-2 infection has also been associated with changes in the lipid composition in cell membranes facilitating viral entry. Additionally, SARS-CoV-2 infections have been linked to heterologous T-cell immunity against common bacterial infections. Moreover, it has been established that SARS-CoV-2 share pathways with several pathogenic protozoans.

In the context of pathways in host tissues and organs, SARS-CoV-2 infections can cause their deregulation and induce innate and adaptive immune responses. Related to the heart, it has been reported that COVID-19 patients have suffered from late-onset cardiovascular complications such as myocarditis-like alterations. Moreover, other organs affected are lung, kidney, liver, brain, eye, and skin.

Much attention has focused on comorbidity issues related to SARS-CoV-2 infections and the long-term consequences of COVID-19. In the context of diabetes, several studies have indicated a high prevalence of COVID-19 in diabetics probably due to compromised IFN responses, damaged caused to DNA by elevated IL-6 levels, and a potential association between ACE2 and control of hyperglycemia. COVID-19 has also been linked to abnormal clotting, thrombosis, and microvascular lesions due to abnormal expression of cytokines and chemokines. Furthermore, it has been shown that in COVID-19 patients with ARDS, microvascular thrombosis might be responsible for the high mortality rate. Heart failure and arrhythmia are comorbid cardiovascular diseases generating complications in COVID-19 patients. Also, as hypertension has been associated with a significantly higher risk of respiratory infection, it influences the severity of COVID-19. Renal injury and induced death of tubular epithelial cells have been linked to enhanced COVID-19 mortality. Moreover, accumulation of SARS-CoV-2 antigens in renal tubules has been discovered in post-mortem kidneys. COVID-19 has also caused long-term effects in the central and peripheral nervous systems. SARS-CoV-2 has been shown to be responsible for the production of inflammatory molecules such as cytokines, chemokines and other inflammatory agents in stimulated glial cells. In the area of ophthalmology, it has been demonstrated that COVID-19 enhances the risk of developing AMD due to the elevated levels of pro-inflammatory cytokines such as IL-6 and TNF-α receptor 2. In the context of cancers, patients who have received anti-cancer drugs may have an increased risk of acquiring severe COVID-19, although enhanced susceptibility to SARS-CoV-2 infections has not been confirmed, so far. Finally, related to autoimmune diseases, although SARS-CoV-2 infections induce inflammatory cytokines, which might assist in fighting viral infections, the enhanced inflammatory chemokine production might provoke an “inflammatory storm”, which could worsen the prognosis of the patient.

In the context of SARS-CoV-2 signaling and cell proliferation and apoptosis, viruses are capable of altering the host cell cycle, taking over the host cell translation machinery, and reducing apoptosis by through interaction with signaling pathways and reprogramming host epigenetic markers. Specific DNA and RNA viruses have been demonstrated to activate cellular oncogenes or inhibit tumor suppression. Investigation of protein-protein interaction on a systemwide scale might allow identification of key components for viral pathogens and cancers. Finally, as programmed cell death, mainly controlled by the DD superfamily proteins, plays a crucial role in SARS-CoV-2 infections, targeting cell death pathways could be essential for controlling viral infections and inflammation, and for restoring the innate immune responses.

In this review, we have demonstrated the importance of the COVID-19 signalome by describing various pathways involved in SARS-CoV-2 infection and their impact on COVID-19 comorbidity. Although plenty of knowledge has been acquired since the appearance of the SARS-CoV-2 at the end of 2019, additional information is required for more effective COVID-19 treatment with a possibility for its complete eradication. As it looks now, we have entered a phase where SARS-CoV-2 has become endemic and to cope with it and be prepared for any novel emerging outbreaks we need to be alert and up to date with the latest information.

Author contributions

All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional review board statement

Not applicable.

Informed consent statement

Not applicable.

Data availability statement

Not applicable.

CRediT authorship contribution statement

Kenneth Lundstrom: Writing – review & editing, Writing – original draft, Conceptualization. Altijana Hromić-Jahjefendić: Writing – review & editing, Writing – original draft, Conceptualization. Esma Bilajac: Writing – original draft. Alaa A.A. Aljabali: Writing – original draft. Katarina Baralić: Writing – original draft. Nagwa A. Sabri: Writing – original draft. Eslam M. Shehata: Writing – original draft. Mohamed Raslan: Writing – original draft. Ana Cláudia B.H. Ferreira: Writing – original draft. Ángel Serrano-Aroca: Writing – original draft. Murtaza M. Tambuwala: Writing – original draft. Vladimir N. Uversky: Writing – original draft. Vasco Azevedo: Writing – original draft. Khalid J. Alzahrani: Writing – original draft. Khalaf F. Alsharif: Writing – original draft. Ibrahim F. Halawani: Writing – original draft. Fuad M. Alzahrani: Writing – original draft. Debmalya Barh: Conceptualization, Project administration, Supervision, Writing – review & editing, Writing – original draft.

Declaration of Competing Interest

The authors declare no conflict of interest.

References

1 Hu B. Guo H. Zhou P. Shi Z.-L. Characteristics of SARS-CoV-2 and COVID-19 Nat. Rev. Microbiol. 2020 1 14 10.1038/s41579-020-00459-7 33024307 PMC7537588

2 Battagello D.S. Dragunas G. Klein M.O. Ayub A.L.P. Velloso F.J. Correa R.G. Unpuzzling COVID-19: tissue-related signaling pathways associated with SARS-CoV-2 infection and transmission Clin. Sci. (Lond.) 134 2020 2137 2160 10.1042/CS20200904 32820801 PMC7443512

3 Harmer D. Gilbert M. Borman R. Clark K.L. Quantitative MRNA expression profiling of ACE 2, a novel homologue of angiotensin converting enzyme FEBS Lett. 532 2002 107 110 10.1016/S0014-5793(02)03640-2 12459472

4 Hamming I. Timens W. Bulthuis M. Lely A. Navis G. van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis J. Pathol. 203 2004 631 637 10.1002/path.1570 15141377 PMC7167720

5 Kuba K. Imai Y. Rao S. Gao H. Guo F. Guan B. Huan Y. Yang P. Zhang Y. Deng W. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus–induced lung injury Nat. Med. 11 2005 875 879 10.1038/nm1267 16007097 PMC7095783

6 Zhang H. Penninger J.M. Li Y. Zhong N. Slutsky A.S. Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target Intensive Care Med. 46 2020 586 10.1007/s00134-020-05985-9 32125455 PMC7079879

7 Cao, Z.; Wu, Y.; Faucon, E.; Sabatier, J.-M. SARS-CoV-2 & Covid-19: key-roles of the ‘renin-angiotensin’ system / vitamin D impacting drug and vaccine developments. Infect. Disord. Drug Targets 20, 348–349. 10.2174/1871526520999200505174704 32370727

8 Zhang Z. Chen L. Zhong J. Gao P. Oudit G.Y. ACE2/Ang-(1–7) signaling and vascular remodeling Sci. China Life Sci. 57 2014 802 808 10.1007/s11427-014-4693-3 25104453

9 McGonagle D. Sharif K. O’Regan A. Bridgewood C. The role of cytokines including interleukin-6 in COVID-19 induced pneumonia and macrophage activation syndrome-like disease Autoimmun. Rev. 19 2020 102537 10.1016/j.autrev.2020.102537 32251717 PMC7195002

10 Ye Q. Wang B. Mao J. The pathogenesis and treatment of the `cytokine storm’ in COVID-19 J. Infect. 80 2020 607 613 10.1016/j.jinf.2020.03.037 32283152 PMC7194613

11 Jose R.J. Manuel A. COVID-19 cytokine storm: the interplay between inflammation and coagulation Lancet Respir. Med. 2020 10.1016/S2213-2600(20)30216-2 PMC7185942 32353251

12 Zhang J. Kennedy A. Xing L. Bui S. Reid W. Joppich J. Ahat E. Rose M. Tang Q. Tai A.W. SARS-CoV-2 triggers Golgi fragmentation via down-regulation of GRASP55 to facilitate viral trafficking bioRxiv 2022 10.1101/2022.03.04.483074 2022.03.04.483074

13 Ghasemnejad-Berenji M. Pashapour S. SARS-CoV-2 and the possible role of Raf/MEK/ERK pathway in viral survival: is this a potential therapeutic strategy for COVID-19? PHA 106 2021 119 122 10.1159/000511280 PMC7573895 33011728

14 Bruzzone C. Bizkarguenaga M. Gil-Redondo R. Diercks T. Arana E. García de Vicuña A. Seco M. Bosch A. Palazón A. San Juan I. SARS-CoV-2 infection dysregulates the metabolomic and lipidomic profiles of serum iScience 23 2020 101645 10.1016/j.isci.2020.101645 33043283 PMC7534591

15 Meoni G. Ghini V. Maggi L. Vignoli A. Mazzoni A. Salvati L. Capone M. Vanni A. Tenori L. Fontanari P. Metabolomic/lipidomic profiling of COVID-19 and individual response to tocilizumab PLoS Pathog. 17 2021 10.1371/journal.ppat.1009243 e1009243 PMC7877736 33524041

16 Barberis E. Timo S. Amede E. Vanella V.V. Puricelli C. Cappellano G. Raineri D. Cittone M.G. Rizzi E. Pedrinelli A.R. Large-scale plasma analysis revealed new mechanisms and molecules associated with the host response to SARS-CoV-2 Int. J. Mol. Sci. 21 2020 8623 10.3390/ijms21228623 33207699 PMC7696386

17 Kimhofer T. Lodge S. Whiley L. Gray N. Loo R.L. Lawler N.G. Nitschke P. Bong S.-H. Morrison D.L. Begum S. Integrative modeling of quantitative plasma lipoprotein, metabolic, and amino acid data reveals a multiorgan pathological signature of SARS-CoV-2 infection J. Proteome Res. 2020 10.1021/acs.jproteome.0c00519 acs.jproteome.0c00519 32806897

18 Nie X. Qian L. Sun R. Huang B. Dong X. Xiao Q. Zhang Q. Lu T. Yue L. Chen S. Multi-organ proteomic landscape of COVID-19 autopsies Cell 184 2021 10.1016/j.cell.2021.01.004 775-791.e14 PMC7794601 33503446

19 Acosta-Ampudia Y. Monsalve D.M. Rojas M. Rodríguez Y. Gallo J.E. Salazar-Uribe J.C. Santander M.J. Cala M.P. Zapata W. Zapata M.I. COVID-19 convalescent plasma composition and immunological effects in severe patients J. Autoimmun. 118 2021 102598 10.1016/j.jaut.2021.102598 33524876 PMC7826092

20 Xu J. Zhou M. Luo P. Yin Z. Wang S. Liao T. Yang F. Wang Z. Yang D. Peng Y. Plasma metabolomic profiling of patients recovered from coronavirus disease 2019 (COVID-19) with pulmonary sequelae 3 months after discharge Clin. Infect. Dis. Off. Publ. Infect. Dis. Soc. Am. 73 2021 2228 10.1093/cid/ciab147 PMC7929060 33596592

21 Huang C. Wang Y. Li X. Ren L. Zhao J. Hu Y. Zhang L. Fan G. Xu J. Gu X. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China Lancet 395 2020 497 506 10.1016/S0140-6736(20)30183-5 31986264 PMC7159299

22 Hussman J.P. Cellular and molecular pathways of COVID-19 and potential points of therapeutic intervention Front. Pharmacol. 11 2020 1169 10.3389/fphar.2020.01169 32848776 PMC7406916

23 Jackson Lisa A. Anderson Evan J. Rouphael Nadine G. Roberts Paul C. Makhene Mamodikoe Coler Rhea N. McCullough Michele P. Chappell James D. Denison Mark R. Stevens Laura J. Pruijssers Andrea J. McDermott Adrian An mRNA Vaccine against SARS-CoV-2 — Preliminary Report N. Engl. J. Med. 383 2020 1920 1931 10.1056/NEJMoa2022483 32663912 PMC7377258

24 Barh D. Aljabali A.A. Tambuwala M.M. Tiwari S. Serrano-Aroca Á. Alzahrani K.J. Silva Andrade B. Azevedo V. Ganguly N.K. Lundstrom K. Predicting COVID-19—comorbidity pathway crosstalk-based targets and drugs: towards personalized COVID-19 management Biomedicines 9 2021 556 10.3390/biomedicines9050556 34067609 PMC8156524

25 Sacchi M.C. Tamiazzo S. Stobbione P. Agatea L. De Gaspari P. Stecca A. Lauritano E.C. Roveta A. Tozzoli R. Guaschino R. SARS-CoV-2 infection as a trigger of autoimmune response Clin. Transl. Sci. 14 2021 898 907 10.1111/cts.12953 33306235 PMC8212749

26 Tutuncuoglu B. Cakir M. Batra J. Bouhaddou M. Eckhardt M. Gordon D.E. Krogan N.J. The landscape of human cancer proteins targeted by SARS-CoV-2 Cancer Discov. 10 2020 916 921 10.1158/2159-8290.CD-20-0559 32444466 PMC7357668

27 Chen Y. Liu Q. Guo D. Emerging coronaviruses: genome structure, replication, and pathogenesis J. Med. Virol. 92 2020 418 423 10.1002/jmv.25681 31967327 PMC7167049

28 Hoffmann M. Kleine-Weber H. Schroeder S. Krüger N. Herrler T. Erichsen S. Schiergens T.S. Herrler G. Wu N.-H. Nitsche A. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor Cell 181 2020 10.1016/j.cell.2020.02.052 271-280.e8 PMC7102627 32142651

29 McGill A.R. Kahlil R. Dutta R. Green R. Howell M. Mohapatra S. Mohapatra S.S. SARS-CoV-2 immuno-pathogenesis and potential for diverse vaccines and therapies: opportunities and challenges Infect. Dis. Rep. 13 2021 102 125 10.3390/idr13010013 33557330 PMC7931091

30 Dey D. Singh S. Khan S. Martin M. Schnicker N.J. Gakhar L. Pierce B.G. Hasan S.S. An extended motif in the SARS-CoV-2 spike modulates binding and release of host coatomer in retrograde trafficking Commun. Biol. 5 2022 1 13 10.1038/s42003-022-03063-y 35136165 PMC8825798

31 Peyssonnaux C. Eychène A. The Raf/MEK/ERK pathway: new concepts of activation Biol. Cell. 93 2001 53 62 10.1016/S0248-4900(01)01125-X 11730323

32 Liu M. Yang Y. Gu C. Yue Y. Wu K.K. Wu J. Zhu Y. Spike protein of SARS-CoV stimulates cyclooxygenase-2 expression via both calcium-dependent and calcium-independent protein kinase C pathways FASEB J. 21 2007 1586 1596 10.1096/fj.06-6589com 17267381

33 Lei X. Dong X. Ma R. Wang W. Xiao X. Tian Z. Wang C. Wang Y. Li L. Ren L. Activation and evasion of type I interferon responses by SARS-CoV-2 Nat. Commun. 11 2020 3810 10.1038/s41467-020-17665-9 32733001 PMC7392898

34 Blanco-Melo D. Nilsson-Payant B.E. Liu W.-C. Uhl S. Hoagland D. Møller R. Jordan T.X. Oishi K. Panis M. Sachs D. Imbalanced host response to SARS-CoV-2 drives development of COVID-19 Cell 181 2020 10.1016/j.cell.2020.04.026 1036-1045.e9 PMC7227586 32416070

35 Acharya D. Liu G. Gack M.U. Dysregulation of type I interferon responses in COVID-19 Nat. Rev. Immunol. 20 2020 397 10.1038/s41577-020-0346-x 32457522 PMC7249038

36 Zhang Q. Bastard P. Liu Z. Le Pen J. Moncada-Velez M. Chen J. Ogishi M. Sabli I.K.D. Hodeib S. Korol C. Inborn errors of type I IFN Immunity in patients with life-threatening COVID-19 Science 370 2020 10.1126/science.abd4570 eabd4570 PMC7857407 32972995

37 Hoffmann H.-H. Schneider W.M. Rice C.M. Interferons and viruses: an evolutionary arms race of molecular interactions Trends Immunol. 36 2015 124 138 10.1016/j.it.2015.01.004 25704559 PMC4384471

38 Kotenko S.V. Durbin J.E. Contribution of type III interferons to antiviral immunity: location, location, Location J. Biol. Chem. 292 2017 7295 7303 10.1074/jbc.R117.777102 28289095 PMC5418032

39 Hadjadj J. Yatim N. Barnabei L. Corneau A. Boussier J. Smith N. Péré H. Charbit B. Bondet V. Chenevier-Gobeaux C. Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients Science 369 2020 718 724 10.1126/science.abc6027 32661059 PMC7402632

40 Mazewski C. Perez R.E. Fish E.N. Platanias L.C. Type I interferon (IFN)-regulated activation of canonical and non-canonical signaling pathways Front. Immunol. 11 2020 10.3389/fimmu.2020.606456 PMC7719805 33329603

41 Bueno I. Travis D. Gonzalez-Rocha G. Alvarez J. Lima C. Benitez C.G. Phelps N.B.D. Wass B. Johnson T.J. Zhang Q. Antibiotic resistance genes in freshwater trout farms in a watershed in Chile J. Environ. Qual. 48 2019 1462 1471 10.2134/jeq2018.12.0431 31589726

42 Le Bon A. Tough D.F. Links between innate and adaptive immunity via type I interferon Curr. Opin. Immunol. 14 2002 432 436 10.1016/S0952-7915(02)00354-0 12088676

43 Min Y.-Q. Huang M. Sun X. Deng F. Wang H. Ning Y.-J. Immune evasion of SARS-CoV-2 from interferon antiviral system Comput. Struct. Biotechnol. J. 19 2021 4217 4225 10.1016/j.csbj.2021.07.023 34336145 PMC8310780

44 Suryawanshi R.K. Koganti R. Agelidis A. Patil C.D. Shukla D. Dysregulation of cell signaling by SARS-CoV-2 Trends Microbiol. 29 2021 224 237 10.1016/j.tim.2020.12.007 33451855 PMC7836829

45 Theken K.N. Tang S.Y. Sengupta S. FitzGerald G.A. The roles of lipids in SARS-CoV-2 viral replication and the host immune response J. Lipid Res. 62 2021 10.1016/j.jlr.2021.100129 PMC8480132 34599996

46 Mesquita F.S. Abrami L. Sergeeva O. Turelli P. Qing E. Kunz B. Raclot C. Montoya J.P. Abriata L.A. Gallagher T. S-Acylation controls SARS-CoV-2 membrane lipid organization and enhances infectivity Dev. Cell 56 2021 10.1016/j.devcel.2021.09.016 2790-2807.e8 PMC8486083 34599882

47 Zhang R. Li Y. Zhang A.L. Wang Y. Molina M.J. Identifying airborne transmission as the dominant route for the spread of COVID-19 Proc. Natl. Acad. Sci. 117 2020 14857 14863 10.1073/pnas.2009637117 32527856 PMC7334447

48 Key Features of Influenza, SARS-CoV-2 and Other Common Respiratory Viruses. 10.

49 Eggenhuizen P.J. Ng B.H. Chang J. Cheong R.M.Y. Yellapragada A. Wong W.Y. Ting Y.T. Monk J.A. Gan P.-Y. Holdsworth S.R. Heterologous immunity between SARS-CoV-2 and pathogenic bacteria Front. Immunol. 13 2022 821595 35154139 10.3389/fimmu.2022.821595 PMC8829141

50 Barh D. Tiwari S. Weener M.E. Azevedo E. Goes-Neto A. Gromiha M.M. Ghosh P. Multi-omics-based identification of SARS-CoV-2 infection biology and candidate drugs against COVID-19 Comput. Biol. Med. 126 2020 104051 10.1016/j.compbiomed.2020.104051 33131530 PMC7547373

51 Barh D. Tiwari S. Andrade B.S. Weener M.E. Góes-Neto A. Azevedo V. Ghosh P. Blum K. Ganguly N.K. A novel multi-omics-based highly accurate prediction of symptoms, comorbid conditions, and possible long-term complications of COVID-19 Mol. Omics 17 2021 317 337 10.1039/D0MO00189A 33683246

52 Fassan M. Collesei A. Angerilli V. Sbaraglia M. Fortarezza F. Pezzuto F. De Gaspari M. Businello G. Moni M. Rizzo S. Multi-design differential expression profiling of COVID-19 lung autopsy specimens reveals significantly deregulated inflammatory pathways and SFTPC impaired transcription Cells 11 2022 1011 10.3390/cells11061011 35326463 PMC8947344

53 Tay M.Z. Poh C.M. Rénia L. MacAry P.A. Ng L.F.P. The trinity of COVID-19: immunity, inflammation and intervention Nat. Rev. Immunol. 2020 1 12 10.1038/s41577-020-0311-8 32346093 PMC7187672

54 Sodeifian F. Nikfarjam M. Kian N. Mohamed K. Rezaei N. The role of type I interferon in the treatment of COVID-19 J. Med. Virol. 94 2022 63 81 10.1002/jmv.27317 34468995 PMC8662121

55 Doehn J.-M. Tabeling C. Biesen R. Saccomanno J. Madlung E. Pappe E. Gabriel F. Kurth F. Meisel C. Corman V.M. CD169/SIGLEC1 is expressed on circulating monocytes in COVID-19 and expression levels are associated with disease severity Infection 49 2021 757 10.1007/s15010-021-01606-9 33825125 PMC8023546

56 Fischer-Riepe L. Daber N. Schulte-Schrepping J. Carvalho B.C.V.D. Russo A. Pohlen M. Fischer J. Chasan A.I. Wolf M. Ulas T. CD163 expression defines specific, IRF8-dependent, immune-modulatory macrophages in the bone marrow J. Allergy Clin. Immunol. 146 2020 1137 1151 10.1016/j.jaci.2020.02.034 32199911

57 Bourgoin P. Biéchelé G. Ait Belkacem I. Morange P. Malergue F. Role of the interferons in CD64 and CD169 expressions in whole blood: relevance in the balance between viral- or bacterial-oriented immune responses Immun. Inflamm. Dis. 8 2020 106 123 10.1002/iid3.289 32031762 PMC7016842

58 Shchendrygina A. Nagel E. Puntmann V.O. Valbuena-Lopez S. COVID-19 myocarditis and prospective heart failure burden Expert. Rev. Cardiovasc. Ther. 19 2021 5 14 10.1080/14779072.2021.1844005 33119418

59 Bansal M. Cardiovascular disease and COVID-19 Diabetes Metab. Syndr. 14 2020 247 250 10.1016/j.dsx.2020.03.013 32247212 PMC7102662

60 Becker R.C. Anticipating the long-term cardiovascular effects of COVID-19 J. Thromb. Thrombolysis 50 2020 512 524 10.1007/s11239-020-02266-6 32880795 PMC7467860

61 Gassen N.C. Papies J. Bajaj T. Emanuel J. Dethloff F. Chua R.L. Trimpert J. Heinemann N. Niemeyer C. Weege F. SARS-CoV-2-mediated dysregulation of metabolism and autophagy uncovers host-targeting antivirals Nat. Commun. 12 2021 3818 10.1038/s41467-021-24007-w 34155207 PMC8217552

62 Chen X. Wang K. Xing Y. Tu J. Yang X. Zhao Q. Li K. Chen Z. Coronavirus membrane-associated papain-like proteases induce autophagy through interacting with Beclin1 to negatively regulate antiviral innate immunity Protein Cell 5 2014 912 927 10.1007/s13238-014-0104-6 25311841 PMC4259884

63 Zhu H. He L. Beclin 1 biology and its role in heart disease Curr. Cardiol. Rev. 11 2015 229 237 10.2174/1573403X10666141106104606 25373623 PMC4558354

64 Niu T.-K. Cheng Y. Ren X. Yang J.-M. Interaction of beclin 1 with survivin regulates sensitivity of human glioma cells to TRAIL-induced apoptosis FEBS Lett. 584 2010 3519 10.1016/j.febslet.2010.07.018 20638385 PMC3210451

65 Xu Y.-X. Huang C. Liu M. Chen N. Chen W. Yang C. Zhao Y. Li X. Duan J. Liu S. Survivin regulated by autophagy mediates hyperglycemia-induced vascular endothelial cell dysfunction Exp. Cell Res. 364 2018 152 159 10.1016/j.yexcr.2018.01.037 29391151

66 Tu S.P. Quante M. Bhagat G. Takaishi S. Cui G. Yang X.D. Muthuplani S. Shibata W. Fox J.G. Pritchard D.M. Interferon-γ inhibits gastric carcinogenesis by inducing epithelial cell autophagy and T cell apoptosis Cancer Res. 71 2011 4247 4259 10.1158/0008-5472.CAN-10-4009 21512143 PMC3139967

67 Gadotti A.C. de Castro Deus M. Telles J.P. Wind R. Goes M. Garcia Charello Ossoski R. de Padua A.M. de Noronha L. Moreno-Amaral A. Baena C.P. IFN-γ is an independent risk factor associated with mortality in patients with moderate and severe COVID-19 infection Virus Res. 289 2020 198171 10.1016/j.virusres.2020.198171 32979474 PMC7510544

68 Mormile COVID-19 myocarditis and lasting heart damage: is deregulation of the beclin1-survivin axis the critical step of pathogenesis? Expert. Rev. Cardiovasc. Ther. 19 2021 10.1080/14779072.2021.1955352 34253135

69 Hirsch J.S. Ng J.H. Ross D.W. Sharma P. Shah H.H. Barnett R.L. Hazzan A.D. Fishbane S. Jhaveri K.D. acute kidney injury in patients hospitalized with COVID-19 Kidney Int. 98 2020 209 218 10.1016/j.kint.2020.05.006 32416116 PMC7229463

70 Kudose S. Batal I. Santoriello D. Xu K. Barasch J. Peleg Y. Canetta P. Ratner L.E. Marasa M. Gharavi A.G. Kidney biopsy findings in patients with COVID-19 J. Am. Soc. Nephrol. 31 2020 1959 1968 10.1681/ASN.2020060802 32680910 PMC7461665

71 Alexander M.P. Mangalaparthi K.K. Madugundu A.K. Moyer A.M. Adam B.A. Mengel M. Singh S. Herrmann S.M. Rule A.D. Cheek E.H. Acute kidney injury in severe COVID-19 has similarities to sepsis-associated kidney injury: a multi-omics study Mayo Clin. Proc. 96 2021 2561 10.1016/j.mayocp.2021.07.001 34425963 PMC8279954

72 Su H. Yang M. Wan C. Yi L.-X. Tang F. Zhu H.-Y. Yi F. Yang H.-C. Fogo A.B. Nie X. Renal histopathological analysis of 26 postmortem findings of patients with COVID-19 in China Kidney Int. 98 2020 219 227 10.1016/j.kint.2020.04.003 32327202 PMC7194105

73 Ueda N. Ceramide-induced apoptosis in renal tubular cells: a role of mitochondria and sphingosine-1-phoshate Int. J. Mol. Sci. 16 2015 5076 5124 10.3390/ijms16035076 25751724 PMC4394466

74 Caterino M. Gelzo M. Sol S. Fedele R. Annunziata A. Calabrese C. Fiorentino G. D’Abbraccio M. Dell’Isola C. Fusco F.M. Dysregulation of lipid metabolism and pathological inflammation in patients with COVID-19 Sci. Rep. 11 2021 10.1038/s41598-021-82426-7 PMC7859398 33536486

75 de Candia P. Prattichizzo F. Garavelli S. Matarese G. T cells: warriors of SARS-CoV-2 infection Trends Immunol. 42 2021 18 30 10.1016/j.it.2020.11.002 33277181 PMC7664351

76 Weiskopf D. Schmitz K.S. Raadsen M.P. Grifoni A. Okba N.M.A. Endeman H. van den Akker J.P.C. Molenkamp R. Koopmans M.P.G. van Gorp E.C.M. Phenotype and kinetics of SARS-CoV-2-specific T cells in COVID-19 patients with acute respiratory distress syndrome Sci. Immunol. 5 2020 10.1126/sciimmunol.abd2071 PMC7319493 32591408

77 Daly J.L. Simonetti B. Klein K. Chen K.-E. Williamson M.K. Antón-Plágaro C. Shoemark D.K. Simón-Gracia L. Bauer M. Hollandi R. Neuropilin-1 is a host factor for SARS-CoV-2 infection Science 370 2020 861 865 10.1126/science.abd3072 33082294 PMC7612957

78 Cantuti-Castelvetri L. Ojha R. Pedro L.D. Djannatian M. Franz J. Kuivanen S. van der Meer F. Kallio K. Kaya T. Anastasina M. Neuropilin-1 facilitates SARS-CoV-2 cell entry and infectivity Science 370 2020 856 860 10.1126/science.abd2985 33082293 PMC7857391

79 Chen N. Zhou M. Dong X. Qu J. Gong F. Han Y. Qiu Y. Wang J. Liu Y. Wei Y. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study Lancet 395 2020 507 513 10.1016/S0140-6736(20)30211-7 32007143 PMC7135076

80 Sun L.-J. Yu J.-W. Shi Y.-G. Zhang X.-Y. Shu M.-N. Chen M.-Y. Hepatitis C virus core protein induces dysfunction of liver sinusoidal endothelial cell by down-regulation of silent information regulator 1 J. Med. Virol. 90 2018 926 935 10.1002/jmv.25034 29350417

81 Guan W. Ni Z. Hu Y. Liang W. Ou C. He J. Liu L. Shan H. Lei C. Hui D.S.C. Clinical characteristics of coronavirus disease 2019 in China N. Engl. J. Med. 2020 10.1056/NEJMoa2002032 NEJMoa2002032 PMC7092819 32109013

82 Xu Z. Shi L. Wang Y. Zhang J. Huang L. Zhang C. Liu S. Zhao P. Liu H. Zhu L. Pathological findings of COVID-19 associated with acute respiratory distress syndrome Lancet Respir. Med. 8 2020 420 422 10.1016/S2213-2600(20)30076-X 32085846 PMC7164771

83 Benedicto A. García-Kamiruaga I. Arteta B. Neuropilin-1: a feasible link between liver pathologies and COVID-19 World J. Gastroenterol. 27 2021 3516 3529 10.3748/wjg.v27.i24.3516 34239266 PMC8240058

84 Gao Y.-M. Xu G. Wang B. Liu B.-C. Cytokine storm syndrome in coronavirus disease 2019: a narrative review J. Intern. Med. 2020 10.1111/joim.13144 PMC7404514 32696489

85 Hirano T. Murakami M. COVID-19: a new virus, but a familiar receptor and cytokine release syndrome Immunity 52 2020 731 733 10.1016/j.immuni.2020.04.003 32325025 PMC7175868

86 Adlimoghaddam A. Odero G.G. Glazner G. Turner R.S. Albensi B.C. Nilotinib improves bioenergetic profiling in brain astroglia in the 3xTg mouse model of Alzheimer’s disease Aging Dis. 12 2021 441 465 10.14336/AD.2020.0910 33815876 PMC7990369

87 Adlimoghaddam A. Albensi B.C. The nuclear factor kappa B (NF-ΚB) signaling pathway is involved in ammonia-induced mitochondrial dysfunction Mitochondrion 57 2021 63 75 10.1016/j.mito.2020.12.008 33378713

88 Lawrence T. The nuclear factor NF-ΚB pathway in inflammation Cold Spring Harb. Perspect. Biol. 1 2009 10.1101/cshperspect.a001651 a001651 PMC2882124 20457564

89 DeDiego M.L. Nieto-Torres J.L. Regla-Nava J.A. Jimenez-Guardeño J.M. Fernandez-Delgado R. Fett C. Castaño-Rodriguez C. Perlman S. Enjuanes L. Inhibition of NF-ΚB-mediated inflammation in severe acute respiratory syndrome coronavirus-infected mice increases survival J. Virol. 88 2014 913 10.1128/JVI.02576-13 24198408 PMC3911641

90 Dosch S.F. Mahajan S.D. Collins A.R. SARS coronavirus spike protein-induced innate immune response occurs via activation of the NF-ΚB pathway in human monocyte macrophages in vitro Virus Res. 142 2009 19 27 10.1016/j.virusres.2009.01.005 19185596 PMC2699111

91 Devaux C.A. Rolain J.-M. Raoult D. ACE2 receptor polymorphism: susceptibility to SARS-CoV-2, hypertension, multi-organ failure, and COVID-19 disease outcome J. Microbiol. Immunol. Infect. 53 2020 425 435 10.1016/j.jmii.2020.04.015 32414646 PMC7201239

92 Román G.C. Spencer P.S. Reis J. Buguet A. Faris M.E.A. Katrak S.M. Láinez M. Medina M.T. Meshram C. Mizusawa H. The neurology of COVID-19 revisited: a proposal from the environmental neurology specialty group of the world federation of neurology to implement international neurological registries J. Neurol. Sci. 414 2020 116884 10.1016/j.jns.2020.116884 32464367 PMC7204734

93 Wang X. Xu W. Hu G. Xia S. Sun Z. Liu Z. Xie Y. Zhang R. Jiang S. Lu L. SARS-CoV-2 infects T lymphocytes through its spike protein-mediated membrane fusion Cell. Mol. Immunol. 2020 1 3 10.1038/s41423-020-0424-9 PMC7348563 32651469

94 Bacherini D. Biagini I. Lenzetti C. Virgili G. Rizzo S. Giansanti F. The COVID-19 pandemic from an ophthalmologist’s perspective Trends Mol. Med. 26 2020 529 531 10.1016/j.molmed.2020.03.008 32470381 PMC7195312

95 Lu C. Liu X. Jia Z. 2019-NCoV transmission through the ocular surface must not be ignored Lancet 395 2020 10.1016/S0140-6736(20)30313-5 e39 PMC7133551 32035510

96 Sungnak W. Huang N. Bécavin C. Berg M. Queen R. Litvinukova M. Talavera-Lopez C. Maatz H. Reichart D. Sampaziotis F. SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes Nat. Med. 26 2020 681 687 10.1038/s41591-020-0868-6 32327758 PMC8637938

97 Kuri T. Zhang X. Habjan M. Martínez-Sobrido L. García-Sastre A. Yuan Z. Weber F. Interferon priming enables cells to partially overturn the SARS coronavirus-induced block in innate immune activation J. Gen. Virol. 90 2009 2686 2694 10.1099/vir.0.013599-0 19625461 PMC2888313

98 Gautam P. Hamashima K. Chen Y. Zeng Y. Makovoz B. Parikh B.H. Lee H.Y. Lau K.A. Su X. Wong R.C.B. Multi-species single-cell transcriptomic analysis of ocular compartment regulons Nat. Commun. 12 2021 5675 10.1038/s41467-021-25968-8 34584087 PMC8478974

99 Brasier A.R. The nuclear factor-ΚB–interleukin-6 signalling pathway mediating vascular inflammation Cardiovasc. Res. 86 2010 211 218 10.1093/cvr/cvq076 20202975 PMC2912657

100 Gallman A.E. Fassett M.S. Cutaneous pathology of COVID-19 as a window into immunologic mechanisms of disease Dermatol. Clin. 39 2021 533 543 10.1016/j.det.2021.05.008 34556243 PMC8297957

101 Crow M.K. Type I interferon in the pathogenesis of lupus J. Immunol. 192 2014 5459 5468 10.4049/jimmunol.1002795 24907379 PMC4083591

102 Trouillet-Assant S. Viel S. Gaymard A. Pons S. Richard J.-C. Perret M. Villard M. Brengel-Pesce K. Lina B. Mezidi M. Type I IFN immunoprofiling in COVID-19 patients J. Allergy Clin. Immunol. 146 2020 10.1016/j.jaci.2020.04.029 206-208.e2 PMC7189845 32360285

103 Wang E.Y. Mao T. Klein J. Dai Y. Huck J.D. Jaycox J.R. Liu F. Zhou T. Israelow B. Wong P. Diverse functional autoantibodies in patients with COVID-19 Nature 595 2021 283 288 10.1038/s41586-021-03631-y 34010947 PMC13130511

104 Singh A.K. Gupta R. Ghosh A. Misra A. Diabetes in COVID-19: prevalence, pathophysiology, prognosis and practical considerations Diabetes Metab. Syndr. 14 2020 303 310 10.1016/j.dsx.2020.04.004 32298981 PMC7195120

105 Onder G. Rezza G. Brusaferro S. Case-fatality rate and characteristics of patients dying in relation to COVID-19 in Italy JAMA 323 2020 1775 1776 10.1001/jama.2020.4683 32203977

106 Bhatraju P.K. Ghassemieh B.J. Nichols M. Kim R. Jerome K.R. Nalla A.K. Greninger A.L. Pipavath S. Wurfel M.M. Evans L. Covid-19 in critically ill patients in the Seattle Region — case series N. Engl. J. Med. 2020 10.1056/NEJMoa2004500 NEJMoa2004500 PMC7143164 32227758

107 Hussain A. Bhowmik B. do Vale Moreira N.C. COVID-19 and diabetes: knowledge in progress Diabetes Res. Clin. Pract. 162 2020 108142 10.1016/j.diabres.2020.108142 32278764 PMC7144611

108 de Pititto, B. A.; Ferreira, S.R.G. Diabetes and Covid-19: More than the Sum of Two Morbidities. Rev. Saude Publica 54, 54, 10.11606/s1518-8787.2020054002577 . 10.11606/s1518-8787.2020054002577 PMC7243859 32491053

109 Zeng Z. Yu H. Chen H. Qi W. Chen L. Chen G. Yan W. Chen T. Ning Q. Han M. Longitudinal changes of inflammatory parameters and their correlation with disease severity and outcomes in patients with COVID-19 from Wuhan, China Crit. Care 24 2020 525 10.1186/s13054-020-03255-0 32854750 PMC7450961

110 Lee B.-C. Lee J. Cellular and molecular players in adipose tissue inflammation in the development of obesity-induced insulin resistance Biochim. Biophys. Acta 1842 2014 446 462 10.1016/j.bbadis.2013.05.017 23707515 PMC3800253

111 Šestan M. Marinović S. Kavazović I. Cekinović Đ. Wueest S. Turk Wensveen T. Brizić I. Jonjić S. Konrad D. Wensveen F.M. Virus-induced interferon-γ causes insulin resistance in skeletal muscle and derails glycemic control in obesity Immunity 49 2018 10.1016/j.immuni.2018.05.005 164-177.e6 29958802

112 Lu C.-L. Wang Y. Yuan L. Li Y. Li X.-Y. The angiotensin-converting enzyme 2/angiotensin (1-7)/Mas axis protects the function of pancreatic β cells by improving the function of islet microvascular endothelial cells Int. J. Mol. Med. 34 2014 1293 1300 10.3892/ijmm.2014.1917 25175177

113 Yang J.-K. Lin S.-S. Ji X.-J. Guo L.-M. Binding of SARS coronavirus to its receptor damages islets and causes acute diabetes Acta Diabetol. 47 2010 193 199 10.1007/s00592-009-0109-4 19333547 PMC7088164

114 Ali M.A.M. Spinler S.A. COVID-19 and thrombosis: from bench to bedside Trends Cardiovasc. Med. 31 2021 143 160 10.1016/j.tcm.2020.12.004 33338635 PMC7836332

115 Maxwell A.J. Ding J. You Y. Dong Z. Chehade H. Alvero A. Mor Y. Draghici S. Mor G. Identification of key signaling pathways induced by SARS-CoV2 that underlie thrombosis and vascular injury in COVID-19 patients J. Leukoc. Biol. 109 2021 35 47 10.1002/JLB.4COVR0920-552RR 33242368 PMC7753679

116 Chen K. Liu J. Cao X. Regulation of type I interferon signaling in immunity and inflammation: a comprehensive review J. Autoimmun. 83 2017 1 11 10.1016/j.jaut.2017.03.008 28330758

117 Obermayer A. Stoiber W. Krautgartner W.-D. Klappacher M. Kofler B. Steinbacher P. Vitkov L. Grabcanovic-Musija F. Studnicka M. New aspects on the structure of neutrophil extracellular traps from chronic obstructive pulmonary disease and in vitro generation PLoS One 9 2014 10.1371/journal.pone.0097784 e97784 PMC4022649 24831032

118 Narasaraju T. Yang E. Samy R.P. Ng H.H. Poh W.P. Liew A.-A. Phoon M.C. van Rooijen N. Chow V.T. Excessive neutrophils and neutrophil extracellular traps contribute to acute lung injury of influenza pneumonitis Am. J. Pathol. 179 2011 199 210 10.1016/j.ajpath.2011.03.013 21703402 PMC3123873

119 Arabi Y.M. Murthy S. Webb S. COVID-19: a novel coronavirus and a novel challenge for critical care Intensive Care Med. 46 2020 833 836 10.1007/s00134-020-05955-1 32125458 PMC7080134

120 Tang X. Du R.-H. Wang R. Cao T.-Z. Guan L.-L. Yang C.-Q. Zhu Q. Hu M. Li X.-Y. Li Y. Comparison of hospitalized patients with ARDS caused by COVID-19 and H1N1 Chest 158 2020 195 205 10.1016/j.chest.2020.03.032 32224074 PMC7151343

121 Deutsch V.R. Tomer A. Megakaryocyte development and platelet production Br. J. Haematol. 134 2006 453 466 10.1111/j.1365-2141.2006.06215.x 16856888

122 Kaushansky K. Thrombopoietin: the primary regulator of platelet production Blood 86 1995 419 431 7605981

123 Deutsch V.R. Olson T.A. Nagler A. Slavin S. Levine R.F. Eldor A. The response of cord blood megakaryocyte progenitors to IL-3, IL-6 and aplastic canine serum varies with gestational age Br. J. Haematol. 89 1995 8 16 10.1111/j.1365-2141.1995.tb08917.x 7833281

124 Rothan H.A. Byrareddy S.N. The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak J. Autoimmun. 109 2020 102433 10.1016/j.jaut.2020.102433 32113704 PMC7127067

125 Garg S. Kim L. Whitaker M. O’Halloran A. Cummings C. Holstein R. Prill M. Chai S.J. Kirley P.D. Alden N.B. Hospitalization rates and characteristics of patients hospitalized with laboratory-confirmed coronavirus disease 2019 - COVID-NET, 14 states, March 1-30, 2020 MMWR Morb. Mortal. Wkly Rep. 69 2020 458 464 10.15585/mmwr.mm6915e3 32298251 PMC7755063

126 Zhou F. Yu T. Du R. Fan G. Liu Y. Liu Z. Xiang J. Wang Y. Song B. Gu X. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study Lancet 395 2020 1054 1062 10.1016/S0140-6736(20)30566-3 32171076 PMC7270627

127 Tan M. Liu Y. Zhou R. Deng X. Li F. Liang K. Shi Y. Immunopathological characteristics of coronavirus disease 2019 cases in Guangzhou, China Immunology 160 2020 261 268 10.1111/imm.13223 32460357 PMC7283723

128 Tamimi F. Abusamak M. Akkanti B. Chen Z. Yoo S.-H. Karmouty-Quintana H. The case for chronotherapy in Covid-19-induced acute respiratory distress syndrome Br. J. Pharmacol. 177 2020 4845 4850 10.1111/bph.15140 32442317 PMC7280566

129 Norlander A.E. Madhur M.S. Harrison D.G. The immunology of hypertension J. Exp. Med. 215 2018 21 33 10.1084/jem.20171773 29247045 PMC5748862

130 Zeng Q. Li Y.-Z. Dong S.-Y. Chen Z.-T. Gao X.-Y. Zhang H. Huang G. Xu Y. Dynamic SARS-CoV-2-specific immunity in critically ill patients with hypertension Front. Immunol. 11 2020 596684 10.3389/fimmu.2020.596684 33362779 PMC7758245

131 Nakazawa D. Kumar S.V. Marschner J. Desai J. Holderied A. Rath L. Kraft F. Lei Y. Fukasawa Y. Moeckel G.W. Histones and neutrophil extracellular traps enhance tubular necrosis and remote organ injury in ischemic AKI J. Am. Soc. Nephrol. 28 2017 1753 1768 10.1681/ASN.2016080925 28073931 PMC5461800

132 Perico L. Benigni A. Remuzzi G. Should COVID-19 concern nephrologists? Why and to what extent? The emerging impasse of angiotensin blockade Nephron Clin. Pract. 2020 1 9 10.1159/000507305 PMC7179544 32203970

133 Wan S. Yi Q. Fan S. Lv J. Zhang X. Guo L. Lang C. Xiao Q. Xiao K. Yi Z. Relationships among lymphocyte subsets, cytokines, and the pulmonary inflammation index in coronavirus (COVID-19) infected patients Br. J. Haematol. 189 2020 428 437 10.1111/bjh.16659 32297671 PMC7262036

134 Rabi F.A. Al Zoubi M.S. Kasasbeh G.A. Salameh D.M. Al-Nasser A.D. SARS-CoV-2 and coronavirus disease 2019: what we know so far Pathogens 9 2020 E231 10.3390/pathogens9030231 PMC7157541 32245083

135 Li X. Geng M. Peng Y. Meng L. Lu S. Molecular immune pathogenesis and diagnosis of COVID-19 J. Pharm. Anal. 10 2020 102 108 10.1016/j.jpha.2020.03.001 32282863 PMC7104082

136 Desai T.R. Leeper N.J. Hynes K.L. Gewertz B.L. Interleukin-6 causes endothelial barrier dysfunction via the protein kinase C pathway J. Surg. Res. 104 2002 118 123 10.1006/jsre.2002.6415 12020130

137 Meng X.-M. Nikolic-Paterson D.J. Lan H.Y. Inflammatory processes in renal fibrosis Nat. Rev. Nephrol. 10 2014 493 503 10.1038/nrneph.2014.114 24981817

138 Pober J.S. Sessa W.C. Inflammation and the blood microvascular system Cold Spring Harb. Perspect. Biol. 7 2014 10.1101/cshperspect.a016345 a016345 PMC4292166 25384307

139 Pilotto A. Benussi A. Libri I. Masciocchi S. Poli L. Premi E. Alberici A. Baldelli E. Bonacina S. Brambilla L. COVID-19 impact on consecutive neurological patients admitted to the emergency department J. Neurol. Neurosurg. Psychiatry 92 2021 218 220 10.1136/jnnp-2020-323929 33055146

140 Huang C. Huang L. Wang Y. Li X. Ren L. Gu X. Kang L. Guo L. Liu M. Zhou X. 6-month consequences of COVID-19 in patients discharged from hospital: a cohort study Lancet 397 2021 220 232 10.1016/S0140-6736(20)32656-8 33428867 PMC7833295

141 Carfì A. Bernabei R. Landi F. For the gemelli against COVID-19 post-acute care study group persistent symptoms in patients after acute COVID-19 JAMA 324 2020 603 605 10.1001/jama.2020.12603 32644129 PMC7349096

142 Goërtz Y.M.J. Van Herck M. Delbressine J.M. Vaes A.W. Meys R. Machado F.V.C. Houben-Wilke S. Burtin C. Posthuma R. Franssen F.M.E. Persistent symptoms 3 months after a SARS-CoV-2 infection: the post-COVID-19 syndrome? ERJ Open Res. 6 2020 00542 02020 10.1183/23120541.00542-2020 33257910 PMC7491255

143 Pilotto A. Cristillo V. Cotti Piccinelli S. Zoppi N. Bonzi G. Sattin D. Schiavolin S. Raggi A. Canale A. Gipponi S. Long-term neurological manifestations of COVID-19: prevalence and predictive factors Neurol. Sci. 42 2021 4903 4907 10.1007/s10072-021-05586-4 34523082 PMC8439956

144 Taquet M. Geddes J.R. Husain M. Luciano S. Harrison P.J. 6-month neurological and psychiatric outcomes in 236 379 survivors of COVID-19: a retrospective cohort study using electronic health records Lancet Psychiatry 8 2021 416 427 10.1016/S2215-0366(21)00084-5 33836148 PMC8023694

145 Bohmwald K. Gálvez N.M.S. Ríos M. Kalergis A.M. Neurologic alterations due to respiratory virus infections Front. Cell. Neurosci. 12 2018 386 10.3389/fncel.2018.00386 30416428 PMC6212673

146 Pilotto A. Masciocchi S. Volonghi I. De Giuli V. Caprioli F. Mariotto S. Ferrari S. Bozzetti S. Imarisio A. Risi B. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) encephalitis is a cytokine release syndrome: evidences from cerebrospinal fluid analyses Clin. Infect. Dis. 73 2021 e3019 e3026 33395482 10.1093/cid/ciaa1933 PMC7799260

147 Sindhuja K. Lomi N. Asif M.I. Tandon R. Clinical profile and prevalence of conjunctivitis in mild COVID-19 patients in a tertiary care COVID-19 hospital: a retrospective cross-sectional study Indian J. Ophthalmol. 68 2020 1546 1550 10.4103/ijo.IJO_1319_20 32709772 PMC7640841

148 Seddon J.M. George S. Rosner B. Rifai N. Progression of age-related macular degeneration: prospective assessment of C-reactive protein, interleukin 6, and other cardiovascular biomarkers Arch. Ophthalmol. 123 2005 774 782 10.1001/archopht.123.6.774 15955978

149 Mullins R.F. Russell S.R. Anderson D.H. Hageman G.S. Drusen associated with aging and age-related macular degeneration contain proteins common to extracellular deposits associated with atherosclerosis, elastosis, amyloidosis, and dense deposit disease FASEB J. 14 2000 835 846 10783137

150 Ly L.V. Baghat A. Versluis M. Jordanova E.S. Luyten G.P.M. van Rooijen N. van Hall T. van der Velden P.A. Jager M.J. In aged mice, outgrowth of intraocular melanoma depends on proangiogenic M2-type macrophages J. Immunol. 185 2010 3481 3488 10.4049/jimmunol.0903479 20713886

151 Bronkhorst I.H.G. Ly L.V. Jordanova E.S. Vrolijk J. Versluis M. Luyten G.P.M. Jager M.J. Detection of M2-macrophages in uveal melanoma and relation with survival Invest. Ophthalmol. Vis. Sci. 52 2011 643 650 10.1167/iovs.10-5979 20811059

152 Lee L.Y. Cazier J.-B. Angelis V. Arnold R. Bisht V. Campton N.A. Chackathayil J. Cheng V.W. Curley H.M. Fittall M.W. COVID-19 mortality in patients with cancer on chemotherapy or other anticancer treatments: a prospective cohort study Lancet 395 2020 1919 1926 10.1016/S0140-6736(20)31173-9 32473682 PMC7255715

153 Zhang L. Zhu F. Xie L. Wang C. Wang J. Chen R. Jia P. Guan H.Q. Peng L. Chen Y. Clinical characteristics of COVID-19-infected cancer patients: a retrospective case study in three hospitals within Wuhan, China Ann. Oncol. 31 2020 894 10.1016/j.annonc.2020.03.296 32224151 PMC7270947

154 Liang W. Guan W. Chen R. Wang W. Li J. Xu K. Li C. Ai Q. Lu W. Liang H. Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China Lancet Oncol. 21 2020 335 337 10.1016/S1470-2045(20)30096-6 32066541 PMC7159000

155 Kang S. Tanaka T. Narazaki M. Kishimoto T. Targeting interleukin-6 signaling in clinic Immunity 50 2019 1007 1023 10.1016/j.immuni.2019.03.026 30995492

156 Giamarellos-Bourboulis E.J. Netea M.G. Rovina N. Akinosoglou K. Antoniadou A. Antonakos N. Damoraki G. Gkavogianni T. Adami M.-E. Katsaounou P. complex immune dysregulation in COVID-19 patients with severe respiratory failure Cell Host Microbe 27 2020 10.1016/j.chom.2020.04.009 992-1000.e3 PMC7172841 32320677

157 Musella M. Manic G. De Maria R. Vitale I. Sistigu A. Type-I-interferons in infection and cancer: unanticipated dynamics with therapeutic implications Oncoimmunology 6 2017 10.1080/2162402X.2017.1314424 e1314424 PMC5467995 28638743

158 Schreiber R.D. Old L.J. Smyth M.J. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion Science 331 2011 1565 1570 10.1126/science.1203486 21436444

159 Wykes M.N. Lewin S.R. Immune checkpoint blockade in infectious diseases Nat. Rev. Immunol. 18 2018 91 104 10.1038/nri.2017.112 28990586 PMC5991909

160 Zheng M. Gao Y. Wang G. Song G. Liu S. Sun D. Xu Y. Tian Z. Functional exhaustion of antiviral lymphocytes in COVID-19 patients Cell. Mol. Immunol. 17 2020 533 535 10.1038/s41423-020-0402-2 32203188 PMC7091858

161 Ceschi A. Noseda R. Palin K. Verhamme K. Immune checkpoint Inhibitor-related cytokine release syndrome: analysis of WHO global pharmacovigilance database Front. Pharmacol. 11 2020 557 10.3389/fphar.2020.00557 32425791 PMC7212758

162 Betterle C. Le malattie autoimmuni 2017 Piccin Padova 978-88-299-2838-5

163 Bonometti R. Sacchi M.C. Stobbione P. Lauritano E.C. Tamiazzo S. Marchegiani A. Novara E. Molinaro E. Benedetti I. Massone L. Bellora A. Boverio R. The first case of systemic lupus erythematosus (SLE) triggered by COVID-19 infection Eur Rev Med Pharmacol Sci. 24 18 2020 9695 9697 10.26355/eurrev_202009_23060 PMID: 33015814 33015814

164 Infantino M. Damiani A. Gobbi F.L. Grossi V. Lari B. Macchia D. Casprini P. Veneziani F. Villalta D. Bizzaro N. Serological assays for SARS-CoV-2 infectious disease: benefits, limitations and perspectives Isr. Med. Assoc. J. 22 2020 203 210 32286019

165 Channappanavar R. Perlman S. Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology Semin. Immunopathol. 39 2017 529 539 10.1007/s00281-017-0629-x 28466096 PMC7079893

166 Davey N.E. Travé G. Gibson T.J. How viruses hijack cell regulation Trends Biochem. Sci. 36 2011 159 169 10.1016/j.tibs.2010.10.002 21146412

167 Liao J.B. Viruses and human cancer Yale J. Biol. Med. 79 2006 115 122 17940621 PMC1994798

168 Gordon D.E. Jang G.M. Bouhaddou M. Xu J. Obernier K. White K.M. O’Meara M.J. Rezelj V.V. Guo J.Z. Swaney D.L. A SARS-CoV-2 protein interaction map reveals targets for drug-repurposing Nature 583 2020 459 468 10.1038/s41586-020-2286-9 32353859 PMC7431030

169 Xu L.H. Huang M. Fang S.G. Liu D.X. Coronavirus infection induces DNA replication stress partly through interaction of its nonstructural protein 13 with the P125 subunit of DNA polymerase δ J. Biol. Chem. 286 2011 39546 39559 10.1074/jbc.M111.242206 21918226 PMC3234778

170 Yuan X. Yao Z. Wu J. Zhou Y. Shan Y. Dong B. Zhao Z. Hua P. Chen J. Cong Y. G1 phase cell cycle arrest induced by SARS-CoV 3a protein via the cyclin D3/PRb pathway Am. J. Respir. Cell Mol. Biol. 37 2007 9 19 10.1165/rcmb.2005-0345RC 17413032

171 Na H.-K. Surh Y.-J. Oncogenic potential of Nrf2 and its principal target protein heme oxygenase-1 Free Radic. Biol. Med. 67 2014 353 365 10.1016/j.freeradbiomed.2013.10.819 24200599

172 Lu W. Zuo Y. Feng Y. Zhang M. SIRT5 facilitates cancer cell growth and drug resistance in non-small cell lung cancer Tumor Biol. 35 2014 10699 10705 10.1007/s13277-014-2372-4 25070488

173 Hino R. Uozaki H. Murakami N. Ushiku T. Shinozaki A. Ishikawa S. Morikawa T. Nakaya T. Sakatani T. Takada K. Activation of DNA methyltransferase 1 by EBV latent membrane protein 2A leads to promoter hypermethylation of PTEN gene in gastric carcinoma Cancer Res. 69 2009 2766 2774 10.1158/0008-5472.CAN-08-3070 19339266

174 García-Carpizo V. Sarmentero J. Han B. Graña O. Ruiz-Llorente S. Pisano D.G. Serrano M. Brooks H.B. Campbell R.M. Barrero M.J. NSD2 contributes to oncogenic RAS-driven Transcription in lung cancer cells through long-range epigenetic activation Sci. Rep. 6 2016 32952 10.1038/srep32952 27604143 PMC5015087

175 Tian B. Yang J. Zhao Y. Ivanciuc T. Sun H. Garofalo R.P. Brasier A.R. BRD4 couples NF-ΚB/RelA with airway inflammation and the IRF-RIG-I amplification loop in respiratory syncytial virus infection J. Virol. 91 2017 e00007 e00017 10.1128/JVI.00007-17 28077651 PMC5331805

176 Huang C. Lokugamage K.G. Rozovics J.M. Narayanan K. Semler B.L. Makino S. SARS coronavirus Nsp1 protein induces template-dependent endonucleolytic cleavage of MRNAs: viral MRNAs are resistant to Nsp1-induced RNA cleavage PLoS Pathog. 7 2011 10.1371/journal.ppat.1002433 e1002433 PMC3234236 22174690

177 Hong, S.; Freeberg, M.A.; Han, T.; Kamath, A.; Yao, Y.; Fukuda, T.; Suzuki, T.; Kim, J.K.; Inoki, K. LARP1 functions as a molecular switch for MTORC1-mediated translation of an essential class of MRNAs. eLife 6, e25237, 10.7554/eLife.25237 . PMC5484620 28650797

178 Ivanisenko N.V. Seyrek K. Kolchanov N.A. Ivanisenko V.A. Lavrik I.N. The role of death domain proteins in host response upon SARS-CoV-2 infection: modulation of programmed cell death and translational applications Cell Death Dis. 6 2020 1 10 10.1038/s41420-020-00331-w PMC7547561 33072409

179 Park H.H. Lo Y.-C. Lin S.-C. Wang L. Yang J.K. Wu H. The death domain superfamily in intracellular signaling of apoptosis and inflammation Annu. Rev. Immunol. 25 2007 561 586 10.1146/annurev.immunol.25.022106.141656 17201679 PMC2904440

180 Wilson N.S. Dixit V. Ashkenazi A. Death receptor signal transducers: nodes of coordination in immune signaling networks Nat. Immunol. 10 2009 348 355 10.1038/ni.1714 19295631

181 Ren Y. Shu T. Wu D. Mu J. Wang C. Huang M. Han Y. Zhang X.-Y. Zhou W. Qiu Y. The ORF3a protein of SARS-CoV-2 induces apoptosis in cells Cell. Mol. Immunol. 17 2020 881 883 10.1038/s41423-020-0485-9 32555321 PMC7301057

Data availability

No data was used for the research described in the article.

Acknowledgments

Not applicable.