Extended host range of SARS-CoV-2 mutants of concern

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) from China continues to cause new infections worldwide, causing coronavirus disease 2019 (COVID-19) The emergence of several new variants of is demonstrated. These are, in some cases, associated with increased transmissibility and / or antigenic escape. Now, the new preprint suggests that the range of hosts that can be infected with the virus can also be expanded.

study: The SARS-CoV-2 mutants of concern alpha, beta, gamma and delta have expanded the host range of ACE2 receptors. Image Credit: CI Photos / Shutterstock

The preprinted version of this survey is bioRxiv* Servers and articles have been peer reviewed.

Background

Beta coronavirus SARS-CoV-2 is believed to have emerged from a bat reservoir. It has been shown to be involved in mammalian cells via the angiotensin converting enzyme 2 (ACE2) receptor on the host cell membrane. According to many scientists, unknown intermediate hosts may be involved in species jumps.

Closely related species such as early SARS-CoV and RaTG13 also derive from bats and support this hypothesis. In addition, the salvecovirus recently identified in bats has been found to be nearly identical to this virus in the spike region of the receptor binding domain (RBD).The results of these findings are from other sources. coronavirus Currently, it has a high affinity for the human ACE2 molecule that circulates in wildlife populations such as bats.

In addition, it is ly possible to infect ferrets, mice, bats, monkeys, chimpanzees, cats, dogs and minks with these viruses, and the host range of these viruses can actually be wider than in bats and humans. It is shown. This discovery has three implications.

For one, it indicates an ongoing risk of transmission from wild animals or livestock to humans, which act as a reservoir of virus, from which repeated waves of infection can occur. Second, the virus can spread between different animal species themselves. Third, such animals, as COVID-19 model animals, may be useful for exploring the development of therapeutic and vaccine platforms and for better understanding of the disease itself.

In early experiments by current authors and other scientists, SARS-CoV-2 Spike protein It can bind to several different types of ACE2 molecules in mammals. In addition, pseudoviral experiments have shown the ability of this peplomer to infect dogs, cats, pangolins, rabbits and other mammals, but not to the same extent in rats, ferrets, certain birds and bats. ..

Hundreds of mutations have occurred in the ribonucleic acid (RNA) genome as the virus rapidly spreads and replicates to human populations around the world. Many of these affect RBD, altering the shape of the epitope and altering recognition by the immune and host cell receptors ACE2.

Some of these are clustered into specific viral variants or strains, forming a Variant of Concern (VOC) such as alpha, beta, gamma, and delta. Alpha VOCs have become world-famous for their remarkably high transmission rates and have almost wiped out the previously dominant D614G strain.

Similarly, Delta stocks rapidly gained dominance in the second quarter of 2021 and replaced most previously circulating stocks. This type of substitution is due to the ability of the virus to continuously adapt to the human host and to evade the host’s immune response by sliding under the immune radar thanks to mutations in the appropriate location of the spike antigen. Due to the increase. Especially RBD.

Spike mutations are also known to positively affect a virus’s ability to replicate, its infectivity, and its ability to antagonize innate immune host responses. The current preprint examined the binding of four VOC spike variants to different species of ACE2 receptors.

What did the study show?

Researchers used a pseudoviral infection experiment in which virus particles expressed four different spike antigens from the four VOCs above. They compared spike-ACE2 binding across multiple hosts to binding of the original or wild-type SARS-CoV-2 spike. Peplomers are designed to enhance uptake into viral particles, which may improve the efficiency of infection.

We evaluated ACE2 molecules in humans, civets, ferrets, mice, hamsters, rats, and pigs for viral orientation. The first two were known hosts, but in current or previous developments, rodents except rats were ly infected and used as a model for the virus. Rats may be a reservoir of human-derived SARS-CoV-2 because their habitat is in close contact with the virus in human sewage. Pigs are known to be a reservoir of Nipah and influenza viruses.

In human ACE2, the pseudo-virus showed only a slight increase in binding to the beta variant compared to wild-type spikes, but not to other viruses. In civets, beta VOCs were the only ones that showed a significant increase in the degree of viral cell invasion.

Mouse ACE2 binding is significantly improved in all four VOCs, supporting the difficulty of achieving infection with this receptor using virus isolates from the early stages of the pandemic. The only delta mutant that did not show the presence of N501Y showed less increase in mouse ACE2 binding than other VOC spikes. In rat ACE2, non-delta VOCs also showed a marked increase in ACE2 receptor binding.

Changes in ferret ACE2 binding were seen in the form of increased binding to beta and gamma VOCs, but no significant changes were observed in hamster or porcine ACE2. The latter has been shown to easily infect wild-type isolates, unlike rats, mice, ferrets and civets.

Therefore, VOCs containing the N501Y mutation have a broader range of hosts, and Delta variants share a similar range to wild-type viruses, including D614G.

Introduction into wild-type virus enabled infection equivalent to Alpha VOC with this mutation, clearly demonstrating the role of the N501Y mutation in overcoming host receptor restriction in mouse ACE2-expressing cells. Changes at other sites such as the furin cleavage site, P681H, or the Δ69-70 deletion of the N-terminal domain (NTD) as seen with alpha VOCs did not appear to alter the viral entry kinetics of mouse or rat ACE2. is. Deletions were not independently investigated, but expressed cells.

In civets, the N501Y and K417N mutations appeared to inhibit viral attachment, but E484K enhances viral entry, which may contribute to a slight increase in ACE2 binding to beta VOC spikes. When introduced into the alpha spike variant, E484K compensated for the inhibition caused by the former mutation.

What is the impact?

This study demonstrates the importance of understanding peplomer-mediated functional changes such as viral entry, widening of host receptor range, and antigenic escape. These can lead to higher infectivity, infectivity, and pathogenicity. The findings of this paper focus on the potential for reverse zoonotic disease in which SARS-CoV-2 is replicated in wildlife species and eventually leaks to human populations.

The few mutations observed that underlie significant functional changes are evidence of the importance of viral evolution between and within hosts.

For now, researchers say:These VOCs are not yet associated with a significant increase in spillover to ACE2 protein in livestock, companion animals, or wildlife... “

This may be due to inadequate sampling of potential reservoir species or limited human-animal contact in infectious situations. Alternatively, spillover may occur very infrequently, or animal infections with these VOCs may not make a significant difference in the characteristics of the disease.

All four VOCs can overcome the relative lack of ability involved in mouse ACE2 and require small spike protein changes to allow spikes to bind to different species of homologous receptors. I confirmed that there is. This was seen in mink and led to the mass destruction of these animals to prevent the spread of the virus among these animals and potentially to other animals. However, it is important to understand that mink mutations such as Y453F inhibit human ACE2 binding.

The apparent differences shown by individual VOCs that bind to the ACE2 receptor in rats, ferrets, or civets are due to N501Y and E484K substitutions within the RBD.

Animal models used to screen for antivirals or vaccines against SARS-CoV-2 can yield different data on exposure infection rate or pathogenicity, depending on whether they are exposed to wild-type or VOC virus. There is a sex.This can cause confusion about Effectiveness of Such intervention.

Second, ACE2 restriction may promote viral adaptation in animals, which may again cause confusion regarding the actual infectivity of the mutants involved. Hamsters are an exception in this regard.

Finally, the ability of SARS-CoV-2 to infect a wide range of hosts is enhanced by VOCs, but in most cases does not impede infectivity to the original host species. It is unpredictable at this time how long this will last and how it will affect the potential for reverse zoonoses.

Researchers

The possible “worst scenario” of SARS-CoV-2 zoonoses is the immune human population, where the virus colonizes new reservoirs, develops antibody selective pressure, and prolongs antigenic drift... “

*Important Notices

bioRxiv publishes unpeer-reviewed preliminary scientific reports and should not be considered definitive, guide clinical / health-related behaviors, or be treated as established information.