Multiorgan Molecular Landscape of Severe COVID-19 Revealed by Consensus Gene Signatures and RAB8B Targeting.
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Avila Jonathan Peña, Park Peter, Singh Youvika, Amaral Paulo P, Castro Ícaro, Ten-Caten Felipe, Schuch Viviane, Gonçalves André N A, Giddaluru Jeevan, Morais Mauro César Cafundó, Ogava Rodrigo L T, Lubiana Thiago, de Castro Gabriel Amoroso, Aquino Rodrigo, Durão Luiz, Martins Júlia Raspante, Jimenez Leandro, Costa-Martins André G, Gonzalez-Dias Patrícia, Hirata Thiago Dominguez Crespo, Dias Thomaz Lüscher, Peixe Débora Guerra, Simizo Adriana, E Silva Juan Carlo Santos, Vasconcelos Amanda Pereira, Rodrigues Marcelo Berçot, Castelucci Bianca G, Virgillio-da-Silva João Victor, Menezes Larissa, Moraes-Vieira Pedro M, Cabral-Marques Otavio, Nakaya Helder I
Аннотация
Severe COVID-19 involves hyperinflammation and multiorgan pathology, but consistent gene signatures remain elusive. We aimed to identify consensus transcriptomic signatures and molecular mechanisms in severe COVID-19. We performed an integrative analysis of 39 studies spanning 11 tissue types, 1551 bulk RNA-seq samples, and over 2 million single cells. A vote-counting strategy combined with a systems-biology approach was applied to detect consensus differentially expressed genes (DEGs). Pathways related to interferon/TNF-α signaling, hypoxia response, and platelet activation were consistently enriched across data sets. Among consensus DEGs-such as IFITM3, BCL2A1, CAMK2D, and CCR1-RAB8B was prioritized for functional validation based on its recurrence in ~45% of tissues and its known role in vesicle trafficking, a process intimately linked to viral life cycles. Molecular dynamics simulations and in vitro assays in SARS-CoV-2-infected CaCo-2 cells demonstrated that RAB8B modulates VAMP-3 clustering and intracellular trafficking. Silencing of Rab8b-1 and Rab8b-2 reduced viral infection by 30% (p = 0.0302) and 76% (p < 0.001), respectively. This study defines robust consensus signatures and positions RAB8B as a critical host factor and potential therapeutic target in severe COVID-19. Further exploration of RAB8B inhibitors is warranted to explore therapeutic utility. An interactive database at https://covidatlas.sysbio.tools/.