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Autopsy studies further indicate tissue-specific virus diversity, including in immune-privileged sites. Questions remain on the viral dynamics leading to the tissue tropism of SARS-CoV-2, including evolutionary trajectories and functional adaptations that could impact persistence and transmission. In this study, we characterized SARS-CoV-2 genomes from 27 distinct tissues collected from an autopsy case where the patient had a primary immune deficiency. We identified tissue-specific virus genotypes, in some instances coexisting within the same sites, with mutations primarily in the receptor-binding domain of the spike protein. Protein simulations and isolation of infectious virus indicate combinations of spike substitutions that would lead to increased protein stability and stronger binding of the virus to host cells. This highlights the importance of studying patients with weakened immune responses where potential tissue reservoirs provide an environment permissive for SARS-CoV-2 evolution and diversification.<\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>Persistent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in immunocompromised individuals are considered a potential source of new viral variants. Beyond the respiratory tract, the virus can spread within days to organs like the brain, heart, and kidneys, where distinct tissue microenvironments may further drive viral evolution and the emergence of new mutations. In this study, we compared the genetic diversity of SARS-CoV-2 genomic RNA isolated from 27 distinct tissue sites collected from an individual with a weakened immune system. By linking viral population dynamics across these tissue sites, we defined the extent of compartmentalization during multi-organ spread, highlighting how non-respiratory tissues can impact SARS-CoV-2 diversification.<\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/jvi.00857-25","type":"journal-article","created":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T12:48:44Z","timestamp":1761914924000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["Tissue tropism and functional adaptation of the SARS-CoV-2 spike protein in a fatal case of COVID-19"],"prefix":"10.1128","volume":"99","author":[{"given":"Katherine E. 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