Relevance of SARS-CoV-2 related factors ACE2 and TMPRSS2 expressions in gastrointestinal tissue with pathogenesis of digestive symptoms, diabetes-associated mortality, and disease recurrence in COVID-19 patients

Introduction

COVID-19 is caused by a new strain of coronavirus called SARS-coronavirus-2 (SARS-CoV-2), which is a positive sense single strand RNA virus. In humans, it binds to angiotensin converting enzyme 2 (ACE2) with the help a structural protein on its surface called the S-spike. Further, cleavage of the viral spike protein (S) by the proteases like transmembrane serine protease 2 (TMPRSS2) or Cathepsin L (CTSL) is essential to effectuate host cell membrane fusion and virus infectivity. COVID-19 poses intriguing issues with imperative relevance to clinicians. The pathogenesis of GI symptoms, diabetes-associated mortality, and disease recurrence in COVID-19 are of particular relevance because they cannot be sufficiently explained from the existing knowledge of the viral diseases. Tissue specific variations of SARS-CoV-2 cell entry related receptors expression in healthy individuals can help in understanding the pathophysiological basis the aforementioned collection of symptoms.

Materials and Methods

The data were downloaded from the Human Protein Atlas available at (<ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="https://www.proteinatlas.org/humanproteome/sars-cov-2">https://www.proteinatlas.org/humanproteome/sars-cov-2</ext-link>) and the tissue specific expressions (both mRNA and protein) of ACE2 and TMPRSS2 as yielded from the studies with RNA sequencing and immunohistochemistry (IHC) were analyzed as a function of the various components of the digestive tract. A digestive system specific functional enrichment map of ACE2 gene was created using g:profiler (<ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="https://biit.cs.ut.ee/gprofiler/gost">https://biit.cs.ut.ee/gprofiler/gost</ext-link>) utility and the data were visualized using Cytoscape software, version 3.7.2 (<ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="https://cytoscape.org/">https://cytoscape.org/</ext-link>).

Results

The correlated expression (transcriptomic and proteomic) of ACE2 (to which SARS-CoV-2 binds through the S-spike) was found to be enriched in the lower gastrointestinal tract (GIT) (highest in small intestine, followed by colon and rectum), and was undetectable in the upper GIT components: mouth cavity (tongue, oral mucosa, and salivary glands), esophagus, and stomach. High expression of ACE2 was noted in the glandular cells as well as in the enterocytes in the lining epithelium (including brush border epithelium). Among other digestive system organs, Gall bladder (GB) showed high expression of ACE2 in glandular cells, while any protein expression was undetectable in liver and pancreas. TMPRSS2 was found enhanced in GIT and exocrine glands of pancreas, and co-localized with ACE2 in enterocytes.

Conclusions

Based on the findings of this study and supportive evidence from the literature we propose that a SARS-CoV-2 binding with ACE2 mediates dysregulation of the sodium dependent nutrient transporters and hence may be a plausible basis for the digestive symptoms in COVID-19 patients. ACE2 mediated dysregulation of sodium dependent glucose transporter (SGLT1 or SLC5A1) in the intestinal epithelium also links it to the pathogenesis of diabetes mellitus which can be a possible reason for the associated mortality in COVID-19 patients with diabetes. High expression of ACE2 in mucosal cells of the intestine and GB make these organs potential sites for the virus entry and replication. Continued replication of the virus at these ACE2 enriched sites may be a basis for the disease recurrence reported in some, thought to be cured, patients.

Graphical Abstract