Organ-specific genome diversity of replication-competent SARS-CoV-2

Abstract The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has gripped the world for over a year1,2. SARS-CoV-2 impacts people on a broad clinical spectrum from asymptomatic to severe respiratory and systemic manifestations resulting in death3. In addition, intra-host SARS-CoV-2 genomic plasticity periodically leads to emergence of new virus variants with higher transmission capacities4–6. Autopsy series have revealed several pathways to death in COVID-19 patients, including respiratory and multi-organ failure, and evidence of SARS-CoV-2 in various organs besides the lungs7,8. However, these studies did not demonstrate the presence of infectious virus in extrapulmonary sites nor did they investigate viral intra-host evolution across multiple organs. Here we report a detailed virological analysis of thirteen postmortem COVID-19 cases that confirms two stages of fatal disease evolution based on disease duration and viral loads in lungs and plasma9. More importantly, the study is the first to provide proof of viremia and presence of replication-competent SARS-CoV-2 in extrapulmonary organs of an immunocompromised patient, accompanied by tissue-specific patterns of genome diversity in organ-resident SARS-CoV-2 populations. In parallel, potentially more transmissible and virulent strains were detected in multiple organs, including identification of mutations N501Y, T1027I, and Y453F in spike (S) protein. These mutations are hallmarks of more contagious United Kingdom (lineage B.1.1.7), South African (lineage B.1.351), Brazilian (lineage P1 and B.1.1.248) or mink variants4,10. Our results provide novel insights about the pathogenesis of SARS-CoV-2 and highlight that COVID-19 treatment and hygiene measures need to be tailored to specific needs of immunocompromised patients.