Cellular Tropism of SARS-CoV-2 across Human Tissues and Age-related Expression of ACE2 and TMPRSS2 in Immune-inflammatory Stromal Cells

Recently, emerging evidence has indicated that COVID-19 represents a major threat to older populations, but the underlying mechanisms remain unclear. The pathogen causing COVID-19 is acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 infection depends on the key entry factors, angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2). Recognizing the importance of ACE2 and TMPRSS2 for the cellular tropism of SARS-CoV-2, we analyzed and presented the landscape of cell-type identities for ACE2(+)TMPRSS2(+) cells across different human tissues and the age-related alterations in ACE2 and TMPRSS2 expression across different cell types. Additionally, most of the post-acute COVID-19 sequelae could attribute to the ACE2-expressing organ systems. Therefore, these SARS-CoV-2 tropism data should be an essential resource for guiding clinical treatment and pathological studies, which should draw attention toward the prioritization of COVID-19 research in the future. Notably, we discovered the age-related expression of ACE2 and TMPRSS2 in the immune-inflammatory stromal cells, implying the potential interplay between COVID-19, stromal cells, and aging. In this study, we developed a novel and practical analsis framework for mapping the cellular tropism of SARS-CoV-2. This approach was built to aid the identification of viral-specific cell types and age-related alterations of viral tropism, highlighting the power of single-cell RNA sequencing (scRNA-seq) to address viral pathogenesis systematically. With the rapid accumulation of scRNA-seq data and the continuously increasing insight into viral entry factors, we anticipate that this scRNA-seq-based approach will attract broader interest in the virus research communities.