Abstract:
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/.
Referência:
AVILA, Jonathan Peña; PARK, Peter; SINGH, Youvika; AMARAL, Paulo P.; CASTRO, Ícaro; TEM-CATEN, Felipe; SCHUCH, Viviane; GONÇALVES, André N.A.; GIDDALURU, Jeevan; MORAIS, Mauro César Cafubndío; OGAVA, Rodrigo L.T.; LUBINA, Thiago; CASTRO, Gabriel Amoroso de; AQUINO, Rodrigo; DURÃO, Luiz; MARTINS, Júlia Raspante; JIMENEZ, Leandro; MARTINS, André Guilherme da Costa; GONZALEZ-Dias, Patrícia; HIRATA, Thiago Dominguez Crespo; DIAS, Thomaz Lüscher; PEIXE, Débora Guerra; SIMIZO, Adriana; SILVA, Juan Carlo Santos e; VASCONCELOS, Amanda Pereira; RODRIGUES, Marcelo Berçot; CASTELUCCI, Bianca G. Castelucci; VIGILLIO-DA-SILVA; João Victor; MENEZES, Larissa; MORAES-VIEIRA, Pedro M.; CABRAL-MARQUES, Otavio; NAKAYA, Helder I. Multiorgan molecular landscape of severe COVID-19 revealed by consensus gene signatures and RAB8B targeting. Journal of Medical Virology, v.98, n.4, 1-17, Apr., 2026.
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