Consensus gene signatures reveal the multi-organ impact of severe COVID-19

• Ano de defesa: 2025
• Autor(a) principal: Avila, Jonathan Peña
• Tipo de documento: Tese
• Tipo de acesso: Acesso aberto
• Idioma: eng
• Instituição de defesa: Biblioteca Digitais de Teses e Dissertações da USP
• Palavras-chave em Português: Assinaturas gênicas consenso; Biologia de sistemas; Consensus gene signatures; COVID-19 grave; SARS-CoV-2; Severe COVID-19; Systems biology; Transcriptômica; Transcriptomics
• Link de acesso: https://www.teses.usp.br/teses/disponiveis/9/9142/tde-06022026-123227/

Severe COVID-19 is characterized by hyperinflammation and multi-organ dysfunction. Nevertheless, reproducible gene expression signatures across tissues have remained poorly defined. In this study, consensus transcriptomic signatures were identified and molecular mechanisms underlying severe disease were investigated. An integrative analysis was conducted on 39 independent studies encompassing 11 tissue types, 1,551 bulk RNA-seq samples, and more than 2 million single cells. Consensus differentially expressed genes (DEGs) were identified through a vote-counting strategy combined with systems-biology approaches. Pathways consistently enriched across datasets were found to include interferon and TNF-α signaling, hypoxia responses, and platelet activation. Among the consensus DEGs—such as IFITM3, BCL2A1, CAMK2D, and CCR1—the vesicle-trafficking regulator RAB8B was prioritized for further study, as it was detected in approximately 45% of analyzed tissues and its functional link to viral replication was observed. A hypoxia-induced SREBF2–RAB8B axis was highlighted by coexpression and regulatory network analyses, suggesting a mechanism through which metabolic and vesicular remodeling may be exploited by SARS-CoV-2. Recruitment of the v-SNARE VAMP-3 by RAB8B and promotion of its coalescence into membrane clusters were supported by molecular-dynamics simulations, in which fewer VAMP-3 clusters were observed in the presence of RAB8B, a configuration likely facilitating endosome fusion. The functional importance of RAB8B was confirmed in Caco-2 cells. Viral load was reduced by approximately 30% with shRAB8B-1 (p = 0.0302) and by approximately 76% with shRAB8B-2 (p = 0.0009) following lentiviral shRNAmediated silencing. RAB8B is thus positioned as a critical host factor supporting SARS-CoV-2 replication and as a potential therapeutic target. Further exploration of RAB8B-directed interventions is warranted to assess their clinical utility in mitigating severe COVID-19