ACE2 May be a Receptor for COVID-19 Virus Entry into the Cells

Because SARS-COV virus has significant similarities to the COVID-19 virus (also called SARS-CoV-2), it is worth comparing the two viruses for similarities to learn about COVID-19.

SARS-CoV has surface spikes that bind to Angiotensin Converting Enzyme 2 (ACE2) and gain entry into human cells. Once inside the human cell, virus downregulates the further expression of ACE2 on cell surface. Importantly, ACE2 surface expression is important to keep inflammatory response in check and low levels of ACE2 results in increased inflammatory response.

It is quite likely that COVID-19 (SARS-CoV-2) also binds to ACE2 receptors. In fact, there is significant homology in the amino acid and gene sequence of virus spikes. Further, the computer-generated 3-D models show similar structure and maintenance of the binding site.

Thus, one can propose a model similar to SARS-CoV where COVID-19 binds to the ACE2 on surface of pulmonary epithelial cells, downregulates these receptors, worsens local inflammatory responses and leads to the lung disease that we see on lung imaging (particularly on CT scans) that is so prevalent in these patients.

Of note, ACE2 is present on the intestinal epithelial cells luminal surface giving another portal of entry for these patients and presence of diarrhea in some patients with COVID-19. Other places where ACE2 expression is particularly high include heart, kidneys, and testes.

While there are several inhibitors of ACE1 in the market and are one of the most commonly prescribed medications for hypertension, these inhibitors don’t work on ACE2. Further, inhibition of ACE2 might potentially lead to worsening of the disease in these patients.

Other methods that can be tested include vaccinations against the viral spike proteins, inhibition of ACE2 downstream pathways such as TMPRSS2, and delivering excessive amounts of ACE2 (or homologues) to saturate viral surface receptors.

The role of ACE2 as potential anti-inflammatory agent in human body makes developing any vaccine or therapeutic drugs challenging as it is difficult to predict the responses inside our bodies. Because ACE2 pathways are not fully discovered yet, the development of effective treatments with minimal adverse effects likely will be challenging.