The role of co-infection in the pathogenesis of acute SARS-CoV-2 infection and development of post-acute sequelae: A perspective

View Publication on PubMed

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Published

November 2025

Journal

eLife

Abstract

A major health challenge resulting from the COVID-19 pandemic is the manifestation of post-acute sequelae of SARS-CoV-2 (PASC). PASC (or Long COVID) is a collective term used for clinical symptoms, various pathologies, and life-quality-changing functional impairments that persist for months to years after the initial SARS-CoV-2 infection. The mechanisms underlying PASC are not understood, although advances have been made in identifying factors that may contribute to long-term pathology. Recent data have emerged, showing an association between SARS-CoV-2 viral persistence and non-SARS-CoV-2 infections (pre-existing, viral reactivation, or new infections) in facilitating or mediating PASC. However, the heterogeneous nature and timing of co-infections have made it challenging to understand, interpret, and contextualize their contribution to PASC. Here, we summarize the impact of potential viral, bacterial, and fungal infections on SARS-CoV-2 pathogenesis, with a focus on their possible roles in the development of PASC. We also provide a framework to understand the mechanisms of PASC and inform basic, translational, and clinical research initiatives, including RECOVER, a large and ongoing research initiative to understand, treat, and prevent Long COVID.

Authors

Timothy J Henrich, Christopher P Montgomery, Joerg Graf, Nahed Ismail, Sindhu Mohandas, Mehul S Suthar, Hassan Brim, John M Coffin, Aayush Pagaria, Jeisac Guzmán Rivera, Urmila Vudali, Paul Keim, Guangming Zhong, Rebecca McGrath, Belinda Edwards, Adolfo García-Sastre, Maria Laura Gennaro

Keywords

PASC; SARS-CoV-2; co-infection; immunology; infectious disease; inflammation; long COVID; microbiology