Receptors of coronaviruses (and what we can learn from bats)

Eight months ago I wrote here about another potential receptor for the unfortunate SARS-CoV-2 virus, namely CD147, a broadly expressed cell surface glycoprotein (so far the only clearly confirmed receptor of this novel human coronavirus is the ectoenzyme ACE2). At the time of writing of my blog article the study by a Chinese laboratory was just a preprint before standard peer review, but apparently even clinical studies had been organized involving the use of CD147 mAbs as potential therapies of covid-19 patients. The study has been properly published in December 2020 (1) with the conclusion that CD147 provides an important target for developing specific and effective drugs against COVID-19. So far, so good. But just less than 2 months later, another study by a British research team has been published, entitled “No evidence for basigin/CD147 as a direct SARS-CoV-2 spike binding receptor” (2). The negative conclusions of this paper are very convincing, so it remains to be seen what are the reasons for such dramatically different results. If any effects of CD147 mAbs are confirmed, these could be explained by some indirect effects, such as immune modulation as opposed to direct blockage of viral invasion through CD147.

In this connection it may be interesting to have a look at surface receptors of other known human coronaviruses. Four of them (HCoV-229E, HCoV-NL63, HCoV-OC43, HCoV-HKU1) cause mild to moderate respiratory infections, while two other (MERS-CoV, SARS-CoV) are more dangerous than SARS-CoV-2. Generally, many infections induce damaging hyperinflammatory responses fueled by both innate and adaptive immune mechanisms. As recently reviewed (3), five of the currently known human coronaviruses use three cell surface metallopeptidases (CD13, CD26, and ACE2) as receptors, whereas the others (HCoV-OC43 and HCoV-HKU1) employ O-acetylated-sialic acid (also prominently present in the glycan part of the metallopeptidases) for cell entry. One might think that the peptidases may be involved in the entry mechanism, but it has been demonstrated that the peptidase activities of the receptors are dispensable. On the other hand these ectoenzymes may enhance the infection indirectly due to their well known involvement in immune modulatory pathways contributing to the pathological hyperinflammatory responses.

Obviously, the present pandemic provides a strong impetus to deeper studies on mechanisms of pathologies caused by various respiratory viruses. Better understanding of this area may bring entirely novel approaches to prevention and therapy of diseases caused by such pathogens. By the way, one interesting aspect is the unique peaceful co-existence of multiple viruses with many bats. Apparently, their immune system evolved a radically different strategy to prevent the damage – tolerance of these viruses instead of potentially self-damaging fight against them, as reviewed in a recent Nature paper (4).

Prof. Václav Hořejší, PhD
Inst. of Molecular Genetics AS CR
VH Profile here...

EXBIO PRODUCTS RELATED TO COVID-19:

Multi-color Flow cytometry kits for monitoring of immune system of COVID-19 patients
Anti-hu CD147 antibody (3 clones in multiple formats available)
Anti-hu CD26 (one clone in multiple formats available)

References:
1. Ke Wang et al.: CD147-spike protein is a novel route for SARS-CoV-2 infection to host cells.  Signal Transduction and Targeted Therapy (2020) 5:283 OPEN ACCESS HERE
2. Jarrod Shilts et al.: No evidence for basigin/CD147 as a direct SARS-CoV-2 spike binding receptor. Scientific Reports (2021) 11:413 OPEN ACCESS HERE  
3. Charan Kumar V. Devarakonda et al.: Coronavirus Receptors as Immune Modulators. J Immunol (2021) 206:5 OPEN ACCESS HERE
4. Aaron T. Irving et al.: Lessons from the host defences of bats, a unique viral reservoir. Nature (2021) 589:363 OPEN ACCESS HERE