Article: ACE2 Receptor Usage Reveals Variation in Susceptibility to SARS-CoV and SARS-CoV-2 Infection Among Bat Species by Yan and colleagues (2021)
Background: As of March 10th, 2021, over 117 million people have been infected by severe acute respiratory coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (COVID-19). Since the start of the COVID-19 pandemic, it has been thought that bats are the original host of SARS-CoV-2, since bats were the natural hosts of SARS-CoV (responsible for 2003 outbreak). Because of this, many people inappropriately fear and attack bats, which results in bat conservation challenges. Identifying the specific bat species that carries the virus is crucial to prevent SARS-CoV-2 from spreading and to predict future outbreaks. For infection to occur, the SARS-COV-2 spike protein (on the surface of the virus) attaches to angiotensin-converting enzyme 2 (ACE2; on the host cell surface) to mediate viral entry into the host cell-- through a lock-and-key method. Humans and bats (Rhinolophus species) have the ACE2 receptor on their cells which allows both to be infected by SARS-CoV-2. Based on the structure of the ACE2 receptor, the natural host of SARS-CoV-2 can be determined. In other words, the more similar the structure of ACE2 in a particular bat species is to humans’ ACE2, the more likely that particular bat species is the natural host of the novel coronavirus. Further, if SARS-CoV-2 has a similar ability to infect a bat cell as a human cell (based on ACE2 structure), then that bat species is more likely to be the natural host.
Methods: Yan and colleagues selected 46 bat species; 28 of the species are common to urban areas and 18 species live in rural areas-- not in close proximity to humans. In-lab, the ACE2 structure of each species was expressed on 293T cells (kidney cells from human embryo). Artificial SARS-CoV and SARS-CoV-2 spike proteins were then exposed to these cells, and the binding of the viral spike protein (key) and species-specific ACE2 structures (lock) were analyzed. Then, the entry of pseudoviruses (i.e., fake virus) expressing SARS-CoV and SARS-CoV-2 spike proteins, respectively, were created to test viral entry. These pseudo-coronaviruses were exposed to 293T cells expressing the species-specific ACE2 proteins. Both the lock-and-key and viral entry analyses were compared to that of human ACE2.
Findings: For the lock-and-key analysis, Yan and colleagues found that 32 and 28 bat species could not allow the binding of SARS-CoV and SARS-CoV-2 spike proteins, respectively. However, the ability to bind the species-specific ACE2 proteins was not associated with the ability of the virus to enter the cell. As such, 24 species did not allow entry of SARS-CoV, 21 species did not allow entry of SARS-CoV-2, and 16 species did not allow entry of either viruses. This suggests that those species are unlikely to be the natural hosts of either or both coronaviruses. Also, the bat species that did not allow viral entry were from both urban and rural areas, suggesting that bat proximity to humans does not predict coronavirus natural hosts.
Conclusions: Despite SARS-CoV-2’s ability to infect through the binding of several different bat species’ ACE2 proteins, bats are still not designated as the natural hosts of the novel coronavirus. In fact, bats might not be the natural host at all. However, because of their association with SARS-CoV and the assumption that they are associated with SARS-CoV-2, they are even more endangered than ever. Over one-third of all bat species are endangered, so it is important for people to understand the uncertainty of their relationship with the pandemic and the consequences of disturbing their habitats. As such, bats play an essential role in pollinating plants, dispersing seeds, and pest control. Further research is required to identify the natural host of SARS-CoV-2 and how the virus ‘spilled over’ from animals to humans.
Figure: Pseudo-SARS-CoV-2 entry via different bat species' ACE2 proteins. (b) Percent entry of pseudo-SARS-CoV-2 through different bat species' ACE2 proteins compared to human ACE2 (grey bar; 100%). (c) More red represents more infection of pseudo-SARS-CoV-2 for that specific bat species. Mock represents no infection.
Reference:
Yan, Huan, et al. "ACE2 receptor usage reveals variation in susceptibility to SARS-CoV and SARS-CoV-2 infection among bat species." Nature ecology & evolution.
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