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Since its discovery \u223c40 years ago, research into tenascin-C biology continues to reveal novel functions, the most recent of all being its immunomodulatory activity, especially its role in infection, which is just now beginning to emerge. Here, we explore the role of tenascin-C in the immune response to viruses, including SARS-CoV-2 and HIV-1. Recently, tenascin-C has emerged as a biomarker of disease severity during COVID-19 and other viral infections, and we highlight relevant RNA sequencing and proteomic analyses that suggest a correlation between tenascin-C levels and disease severity. Finally, we ask what the function of this protein during viral replication is and propose tenascin-C as an intercellular signal of inflammation shuttled to distal sites via exosomes, a player in the repair and remodeling of infected and damaged tissues during severe infectious disease, as well as a ligand for specific pathogens with distinct implications for the host. <\/jats:p>","DOI":"10.1152\/ajpcell.00333.2022","type":"journal-article","created":{"date-parts":[[2022,12,2]],"date-time":"2022-12-02T14:45:51Z","timestamp":1669992351000},"page":"C1-C9","update-policy":"https:\/\/doi.org\/10.1152\/aps-crossmark-policy","source":"Crossref","is-referenced-by-count":9,"title":["A virological view of tenascin-C in infection"],"prefix":"10.1152","volume":"324","author":[{"given":"Lorena","family":"Zuliani-Alvarez","sequence":"first","affiliation":[{"name":"QBI Coronavirus Research Group, San Francisco, California"},{"name":"Quantitative Biosciences Institute, University of California, San 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