SARS-CoV-2 cellular tropism and direct multiorgan failure in COVID-19 patients: Bioinformatic predictions, experimental observations, and open questions

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (COVID-19), has led to an unprecedented public health emergency worldwide. While common cold symptoms are observed in mild cases, COVID-19 is accompanied by multiorgan failure in severe patients. Organ damage in COVID-19 patients is partially associated with the indirect effects of SARS-CoV-2 infection (e.g., systemic inflammation, hypoxic-ischemic damage, coagulopathy), but early processes in COVID-19 patients that trigger a chain of indirect effects are connected with the direct infection of cells by the virus. To understand the virus transmission routes and the reasons for the wide-spectrum of complications and severe outcomes of COVID-19, it is important to identify the cells targeted by SARS-CoV-2. This review summarizes the major steps of investigation and the most recent findings regarding SARS-CoV-2 cellular tropism and the possible connection between the early stages of infection and multiorgan failure in COVID-19. The SARS-CoV-2 pandemic is the first epidemic in which data extracted from single-cell RNA-seq (scRNA-seq) gene expression data sets have been widely used to predict cellular tropism. The analysis presented here indicates that the SARS-CoV-2 cellular tropism predictions are accurate enough for estimating the potential susceptibility of different cells to SARS-CoV-2 infection; however, it appears that not all susceptible cells may be infected in patients with COVID-19.

Keywords: SARS-CoV-2; cell entry factors; cellular tropism; infection; multiorgan failure; scRNA-seq.

Figure 1

Simplified scheme of SARS‐CoV‐2 entry into cells. The SARS‐CoV‐2 S protein binds to its receptor, ACE2, on the cell surface, but viral entry occurs only after specific digestion by priming proteases (furin, TMPRSS2, cathepsin L). Furin digests S protein into S1 and S2 subunits during viral egress from the infected cell in the trans‐Golgi network/endosomal system. TMPRSS2 or cathepsin L additionally digest the S2 subdomain at the S2′ cleavage site either at the cell surface or inside the endosome, but it seems that the TMPRSS2‐dependent pathway is the major pathway for SARS‐CoV‐2 entry. Omicron variant of SARS‐CoV‐2 enters cells in a TMPRSS2‐independent manner via the endosomal route. Created with BioRender.com. ACE2, angiotensin converting enzyme 2; SARS‐CoV‐2, severe acute respiratory syndrome coronavirus 2; TMPRSS2, transmembrane protease, serine 2.

Figure 2

Major strategies for analyzing individual cell transcriptomes (single‐cell RNA‐seq [scRNA‐seq] approaches) that were used for the analysis of entry factors during the SARS‐CoV‐2 pandemic. Droplet‐based (left column) and plate‐based (full‐length) RNA‐seq (central column) protocols enable the analysis of transcriptomes of individual cells. The bulk RNA‐seq protocol (right column) captures information about transcriptomes of cells selected by any mechanical methods, most often by fluorescence‐activated cell sorting. This approach does not provide information on gene expression in individual cells but allows the assessment of gene expression in cell types of interest. Thus, the usefulness of this method is intermediate between the scRNA‐seq methods and the conventional RNA‐seq of tissue samples. Created with BioRender.com. SARS‐CoV‐2, severe acute respiratory syndrome coronavirus 2.