ACE2 Isn’t Solely Responsible for Covid-19, Which Explains A Lot

The discovery of two new receptors — neuropilin-1 and CD147 — explains why Covid-19 is a mix of respiratory, vascular, nervous, olfactory, and immunological diseases.

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It has been odd right from the start. If SARS-CoV-2 (the novel coronavirus that causes Covid-19) uses the angiotensin-converting enzyme 2 (ACE2) as a receptor to infect cells, then why is it a lung disease when the lungs have low levels of ACE2?

This was determined back in May 2020 in a study finding that alveolar cell type 2 (the primary target of SARS-CoV-2) in the lungs has ACE2 expression that is “4.7-fold lower than the average expression level of all ACE2 expressing cell types,” such as the liver, stomach, ileum, kidney, and colon.

Later, a systematic review published over a month ago further points out that SARS-CoV-2 tend to end up in places not consistent with ACE2 expression levels. Looking at the figure below, organs SARS-CoV-2 tend to localize (e.g., lungs and brain) do not always have high expression of ACE2, and vice-versa.

Trypsteen et al. (2020). Left: Gradient color (purple) indicates low to high evidence for SARS-CoV-2 detection; the highest expression was found in the upper airways, lungs, oral cavity, gastrointestinal tract, and urinary system. Right: Gradient color (orange) indicates low to high evidence for ACE2 expression; the highest expression was detected in the oral cavity, gastrointestinal tract, and the male reproductive system.

“Hence, the SARS-CoV-2 may depend on co-receptor or other auxiliary membrane proteins to facilitate its infection,” authors of the May study hypothesized. Indeed, in the past month, published studies have confirmed additional receptors that SARS-CoV-2 uses to sneak into cells, which are neuropilin-1 and CD147 (or basigin). These two new receptors also tell us why Covid-19 tends to cause problems in the pulmonary, vascular, nervous, olfactory, and immune systems with little or no ACE2 expression.

Neuropilin-1

In 2009, a study discovered that neuropilin-1 could bind to genes with patterns conforming to the C-end rule. Apparently, the genetic sequence of SARS-CoV-2 spike protein also has this C-end rule.