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Mechanism for the isotype dependence of antibody-mediated toxicity in Cryptococcus neoformans-infected mice.

Ab-based therapies have undergone a renaissance in recent years, but infusion-related reactions are a significant clinical problem. Administration of certain mAbs to Swiss Webster mice infected with Cryptococcus neoformans can result in acute lethal toxicity (ALT) characterized by cardiovascular collapse. The ability of a mAb to produce ALT is isotype dependent and occurs with IgG1 but not IgG3. To investigate this phenomenon, we measured spleen and liver cytokine responses and platelet-activating factor (PAF) content in mice given C. neoformans glucuronoxylomannan (GXM) followed by specific A

Respiratory and Thoracic Medicine

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… Definitive diagnosis of cryptococcosis is based on antigen testing or cytologic, histopathologic, or culture demonstration of the organism. … Aspergillosis is less common than cryptococcosis but can be equally devastating. 3 , 102 , 112 Clinical signs of mild disease are similar to those of nasal cryptococcosis. …

A 12-year study of fungal infections in Rio Grande do Sul, Southern Brazil.

BACKGROUND: The number of fungal infections has increased in recent years in Rio Grande do Sul (RS), Brazil. Epidemiological studies are important for proper control of infections. AIMS: To evaluate the etiology of fungal infections in patients in RS, from 2003 to 2015. METHODS: This is a retrospective and longitudinal study carried out at Mycology Department of Central Laboratory of RS; 13,707 samples were evaluated. The variables sex, age, site of infection, and etiologic agent were analyzed. Susceptibility of Candida to fluconazole was tested in isolates from samples collected in 2015 fro

Cryptococcus neoformans ADS lyase is an enzyme essential for virulence whose crystal structure reveals features exploitable in antifungal drug design.

There is significant clinical need for new antifungal agents to manage infections with pathogenic species such as Cryptococcus neoformans Because the purine biosynthesis pathway is essential for many metabolic processes, such as synthesis of DNA and RNA and energy generation, it may represent a potential target for developing new antifungals. Within this pathway, the bifunctional enzyme adenylosuccinate (ADS) lyase plays a role in the formation of the key intermediates inosine monophosphate and AMP involved in the synthesis of ATP and GTP, prompting us to investigate ADS lyase in C. neoformans

Treatment of rats with heat killed cells (HKC) of Cryptococcus neoformans var. grubii induces cellular activation in spleen and lymphatic nodes.

Our previous studies showed that the subcutaneous pretreatment of rats with heat killed cells of Cryptococcus neoformans (HKC) emulsified in complete Freund adjuvant (CFA) promotes protection against an intraperitoneal challenge with viable C. neoformans. In this model, an appropriate activation of adherent peritoneal cells after antigenic treatment is very important for the control of the infection. Here, we investigated the immune response developed in spleen and lymphatic nodes as a result of treatment with HKC-CFA, which might also contribute in the protective phenomenon of this treatment

Cell wall targeting of laccase of Cryptococcus neoformans during infection of mice.

Laccase is a major virulence factor of the pathogenic fungus Cryptococcus neoformans, which afflicts both immunocompetent and immunocompromised individuals. In the present study, laccase was expressed in C. neoformans lac1Delta cells as a fusion protein with an N-terminal green fluorescent protein (GFP) using C. neoformans codon usage. The fusion protein was robustly localized to the cell wall at physiological pH, but it was mislocalized at low pH. Structural analysis of the laccase identified a C-terminal region unique to C. neoformans, and expression studies showed that the region was requir

Distinct stress responses of two functional laccases in Cryptococcus neoformans are revealed in the absence of the thiol-specific antioxidant Tsa1.

Laccases are thought to be important to the virulence of many fungal pathogens by producing melanin, a presumed oxygen radical scavenger. A laccase in Cryptococcus neoformans has been shown to synthesize melanin and contributes to the virulence and the survival in macrophages of this fungal pathogen. One C. neoformans laccase gene, LAC1, previously called CNLAC1, has been extensively studied, and we describe a homologous gene, LAC2, that is found 8 kb away from LAC1 in the genome. In this study we report a role for both laccases, in addition to the thiol peroxidase, Tsa1, in oxidative and nitr

Dissemination of C. neoformans to the central nervous system: role of chemokines, Th1 immunity and leukocyte recruitment.

Cryptococcus neoformans is a fungus that possesses two properties unique for yeast: (1) production of a polysaccharide capsule and (2) neurotropism. The natural route of infection by C. neoformans is the respiratory tract; thus, factors that regulate the development and recruitment of memory Th1 cells and monocytes into the brain are critical for an effective response against disseminated C. neoformans infection. Production of TNFalpha prior to day 7 is required to prevent colonization of the central nervous system (CNS). Th1 type immunity is required to clear established foci. In contrast, Th

Eosinophil-Cryptococcus neoformans interactions in vivo and in vitro.

Eosinophils are components of inflammatory responses to a variety of pathogens. Although a variety of beneficial and harmful functions have been ascribed to these cells, their role in protection against infectious agents remains uncertain. Previous studies have reported eosinophilic pneumonia in mice infected intratracheally with Cryptococcus neoformans. We confirmed this observation and studied the inflammatory response in the lung at day 14 by light and electron microscopy. Immunostaining for glucuronoxylomannan showed isolated cryptococci inside the eosinophilic cuffs. Eosinophils were foun

Role of human alveolar macrophages as antigen-presenting cells in Cryptococcus neoformans infection.

The contribution of human alveolar macrophages (AM) from normal subjects in Cryptococcus neoformans infection was investigated. AM were able to efficiently phagocytize the fungus after opsonization, but killing activity did not occur at an effector-to-target ratio of 10:1 in a 6-h incubation since there was an inhibition of phagosome-lysosome fusion. Moreover, the role of AM as antigen-presenting cells was investigated. Cryptococcus-laden AM were co-cultured with autologous T lymphocytes and lymphoproliferation was determined; a massive blastogenic response of alpha/beta TCR-bearing T lymphocy

Clinical pharmacokinetics of fluconazole in superficial and systemic mycoses.

The bis triazole agent fluconazole is used widely in the treatment of superficial and deep mycoses. A single oral dose of fluconazole 150 mg … results in over 90% clinical cure or improvement for cutaneous mycosis including tinea, pityriasis, cryptococcosis and candidiasis. Prolonged (6 to 12 months) fluconazole 150 mg once a week is needed to treat onychomycosis successfully. Higher oral doses (200 to 400 mg daily) for long periods are generally used to treat deep mycoses such as meningitis, ophthalmi …

Variable Region Identical IgA and IgE to Cryptococcus neoformans Capsular Polysaccharide Manifest Specificity Differences.

In recent years several groups have shown that isotype switching from IgM to IgG to IgA can affect the affinity and specificity of antibodies sharing identical variable (V) regions. However, whether the same applies to IgE is unknown. In this study we compared the fine specificity of V region-identical IgE and IgA to Cryptococcus neoformans capsular polysaccharide and found that these differed in specificity from each other. The IgE and IgA paratopes were probed by nuclear magnetic resonance spectroscopy with (15)N-labeled peptide mimetics of cryptococcal polysaccharide antigen (Ag). IgE was f

Methylation of glycosylated sphingolipid modulates membrane lipid topography and pathogenicity of Cryptococcus neoformans.

In previous studies we showed that the replication of Cryptococcus neoformans in the lung environment is controlled by the glucosylceramide (GlcCer) synthase gene (GCS1), which synthesizes the membrane sphingolipid GlcCer from the C9-methyl ceramide. Here, we studied the effect of the mutation of the sphingolipid C9 methyltransferase gene (SMT1), which adds a methyl group to position 9 of the sphingosine backbone of ceramide. The C. neoformans Δsmt1 mutant does not make C9-methyl ceramide and, thus, any methylated GlcCer. However, it accumulates demethylated ceramide and demethylated GlcCer. T

Innate imprinting by the modified heat-labile toxin of Escherichia coli (LTK63) provides generic protection against lung infectious disease.

In a healthy individual, the lung contains few lymphoid cells. However, amplified immune responses, as exemplified during lung infection, can cause extensive tissue damage. We have previously demonstrated that one lung infection modulates the immunopathological outcome to a subsequent unrelated pathogen. Mimicking heterologous immunity may provide a means of enhancing both innate and acquired immunity. We now show that prior lung administration of a modified heat-labile toxin from Escherichia coli (LTK63) enhances immunity to respiratory syncytial virus, influenza virus, and the fungus Cryptoc

Antibody efficacy in murine pulmonary Cryptococcus neoformans infection: a role for nitric oxide.

We investigated the pathogenesis of pulmonary Cryptococcus neoformans infection and passive Ab efficacy in mice deficient in inducible NO synthase (NOS2(-/-)) and the parental strain. Parental mice lived significantly longer than NOS2(-/-) mice after intratracheal infection, despite having a higher lung fungal burden. Administration of Ab reduced lung CFU in both NOS2(-/-) and parental mice, but prolonged survival and increased the inflammatory response only in parental mice. Ab administration was associated with increased serum nitrite and reduced polysaccharide levels in parental mice. Eosin

Both Th1 and Th2 cytokines affect the ability of monoclonal antibodies to protect mice against Cryptococcus neoformans.

Variable-region-identical mouse immunoglobulin G1 (IgG1), IgG2b, and IgG2a monoclonal antibodies to the capsular polysaccharide of Cryptococcus neoformans prolong the lives of mice infected with this fungus, while IgG3 is either not protective or enhances infection. CD4+ T cells are required for IgG1-mediated protection, and CD8+ T cells are required for IgG3-mediated enhancement. Gamma interferon is required for both effects. These findings revealed that T cells and cytokines play a role in the modulation of cryptococcal infection by antibodies and suggested that it was important to more full

High-resolution CT in renal transplant patients with suspected pulmonary infections.

OBJECTIVE: This prospective study was carried out to assess the usefulness of high-resolution CT (HRCT) of the chest in immunocompromised renal transplant patients with suspected pulmonary infections. MATERIAL AND METHODS: Twenty-one consecutive renal transplant patients with clinically suspected pulmonary infections underwent chest radiography, HRCT and other tests including bronchoalveolar lavage (BAL). HRCT was performed using a high spatial frequency algorithm with 2-mm-thick sections at 10-mm intervals from apices to domes of the diaphragm. The findings on chest radiography and HRCT were

Neurologic manifestations of AIDS: a comparative study of two populations from Mexico and the United States.

Neurologic complications associated with human immunodeficiency virus type 1 (HIV-1) infection vary geographically. To understand the pattern of HIV-associated neurologic complications in Mexico, 120 AIDS patients from Mexico City, Mexico, and 500 AIDS patients from Houston, Texas, were studied cross-sectionally and retrospectively. Neurologic, laboratory, imaging, and pathologic examinations identified 40 Mexican patients and 130 U.S. patients with neurologic complications. Whereas AIDS dementia complex was the most common neurologic manifestation in both groups, intracranial tuberculoma was

Azathioprine for remission maintenance in anti-interferon-γ autoantibody-associated immunodeficiency syndrome- a retrospective single-center cohort study.

BACKGROUND: Anti-interferon-γ autoantibody (Anti-IFN-γ Aab) disease is associated with frequent recurrent infections. Adjunctive immunosuppressive treatment, including rituximab, can achieve disease remission. However, disease relapses and recurrent infections occur after immunosuppressive drugs are discontinued. Azathioprine (AZA) is used for maintenance therapy in many autoimmune diseases with few adverse effects. This study aimed to assess the effectiveness of AZA in maintaining clinical remission in patients with Anti-IFN-γ Aab disease. METHODS: This retrospective observational study was

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… . | 5 (35.7) | 1 (6.7) | 0.080 Talaromyces marneffei | 2 (14.3) | 0 (0.0) | 0.224 VZV | 2 (14.3) | 0 (0.0) | 0.224 HSV | 2 (14.3) | 0 (0.0) | 0.224 CMV | 1 (7.1) | 0 (0.0) | 0.483 Cryptococcosis | 1 (7.1) | 1 (6.7) | 1.000 Histoplasmosis | 1 (7.1) | 0 (0.0) | 0.483 Tuberculosis | 0 (0.0) | 1 (6.7) | … 9.1) | 0.533 No | 4 (100.0) | 10 (90.9) | NTM, n (%) | | | Yes | 1 (25.0) | 1 (9.1) | 0.423 No | 3 (75.0) | 10 (90.9) | TB, n (%) | | | Yes | 0 (0.0) | 1 (9.1) | 0.533 No | 4 (100.0) | 10 (90.9) | Salmonella spp., n (%) | | | Yes | 0 (0.0) | 1 (9.1) | 0.533 No | 4 (100.0) | 10 (90.9) | Cryptococcosis …

Outcomes of primary total hip arthroplasty following septic arthritis of the hip : a case-control study.

AIMS: Septic arthritis of the hip often leads to irreversible osteoarthritis (OA) and the requirement for total hip arthroplasty (THA). The aim of this study was to report the mid-term risk of any infection, periprosthetic joint infection (PJI), aseptic revision, and reoperation in patients with a past history of septic arthritis who underwent THA, compared with a control group of patients who underwent THA for OA. METHODS: We retrospectively identified 256 THAs in 244 patients following septic arthritis of the native hip, which were undertaken between 1969 and 2016 at a single institution. E