Abstract
Sick, male, and older populations are more vulnerable to COVID-19. However, it remains unclear whether a common mechanism exists across different demographic characteristics. SARS-CoV-2 infection is initiated by the specific binding of the viral spike protein to angiotensin-converting enzyme 2 (ACE2). This study analyzed the demographics of pulmonary ACE2 expression, Mendelian randomization (MR) of ACE2 and COVID-19, and comparative tropism of SARS-CoV-2. The key features of SARS-CoV-2 tropism, including pulmonary ACE2 expression and ACE2-expressing cell types, showed distinct subphenotypes associated with the demographics of vulnerable COVID-19 populations, suggesting a hypothesis centered on "ACE2" to explain their interplay. Next, by integrating multiple COVID-19 cohorts of genome-wide association studies (GWASs) and cis-expression quantitative trait loci (cis-eQTLs) of ACE2, MR analysis demonstrated that ACE2 played a causal role in COVID-19 susceptibility and severity, suggesting ACE2 as a promising target for early COVID-19 treatment. Next, by analyzing the expression of host cell receptors using single-cell RNA sequencing (scRNA-seq) data of human lung tissues, comparative tropism analysis showed that SARS-CoV-2 and other respiratory viruses, but not non-respiratory viruses, had remarkably overlapping and enriched cellular tropism in alveolar type 2 (AT2) cells. This finding indicates the possibility of coinfection with SARS-CoV-2 and other respiratory viruses, perhaps implying sociovirology at the cellular level. Moreover, the binding of viral entry proteins to the compatible host cell receptors is under strong natural selection pressure. Therefore, comparative tropism might reveal the footprint of natural selection that shapes the virus population, which provides a novel perspective for understanding zoonotic spillover events.