Researchers warn that SARS-CoV-2 RBD mutations Q498H and R493K could enhance human-animal cross-transmission

Medical News: In a recent study, researchers from Michigan State University-USA and the University of Arkansas-USA have raised concerns over specific mutations in the SARS-CoV-2 virus, particularly mutations Q498H and R493K, which have emerged in certain new Omicron variants and sub-lineages. These mutations, according to the study, may enhance the virus's ability to jump between humans and animals, heightening the risk of future zoonotic infections. This Medical News report will explore the findings in detail, shedding light on the potential implications of these mutations.


Researchers warn that SARS-CoV-2 RBD mutations Q498H and R493K could
enhance human-animal cross-transmission

The Role of Mutations in Viral Transmission
SARS-CoV-2, like all viruses, undergoes mutations as it spreads and evolves. Some of these mutations can enhance the virus’s infectivity in humans, while others may alter its ability to infect animals. The researchers focused on mutations in the virus’s receptor-binding domain (RBD), the region of the spike protein that allows the virus to bind to the ACE2 receptor in host cells. The stronger the bond between the RBD and the ACE2 receptor, the more infectious the virus becomes.
 
Using advanced modeling techniques, including a multitask deep learning model called MT-TopLap, the researchers examined how these RBD mutations might impact the virus’s ability to cross between species. By analyzing binding free energy (BFE) changes, they identified key mutations that could make SARS-CoV-2 more efficient at infecting animals and potentially jumping back to humans.

This article emphasizes that cross-species transmission has been a concern since the early days of the COVID-19 pandemic. The virus is believed to have originated in animals before making the leap to humans. As it continues to evolve, the risk of it jumping to other animal species, such as cats, bats, or deer, and then back to humans remains a possibility. The mutations Q498H and R493K are of particular concern because they may make this process easier.
 
Analyzing the Risk: How RBD Mutations Affect Transmission
The key focus of the study was to understand how these specific RBD mutations might influence SARS-CoV-2’s ability to infect both humans and animals. The MT-TopLap model was trained using deep mutational scanning (DMS) data, allowing it to predict changes in BFE due to mutations across multiple species. The model was able to provide insights into how the virus’s RBD interacts with the ACE2 receptors of not only humans but also animals like cats, bats, deer, and hamsters.
The study’s findings indicated that the mutations Q498H in the SARS-CoV-2 virus and R493K in its BA.2 variant could significantly enhance the virus’s ability to bind to the ACE2 receptors of animals. This enhanced binding suggests that these mutations could increase the virus’s potential for cross-species transmission, making it more likely to jump from humans to animals and vice versa.
 
Moreover, the researchers highlighted that while the virus may adapt to infect animals, this does not necessarily mean it will lose its ability to infect humans. On the contrary, mutations that enhance cross-species transmission may also result in a virus that is better equipped to infect humans after adapting to animal hosts. This is particularly concerning as it could lead to the emergence of new, more infectious variants that are capable of causing outbreaks in both human and animal populations.
 
The Implications of Human-Animal Cross-Transmission
The potential for SARS-CoV-2 to spread between humans and animals presents significant public health challenges. If the virus can establish itself in animal populations, it could create reservoirs from which it might re-emerge, even after human infections have been controlled. This could make it more difficult to fully eradicate the virus and could lead to new outbreaks driven by animal-to-human transmission.
 
In the United States, for example, a significant percentage of white-tailed deer have been found to be infected with SARS-CoV-2, raising concerns that the virus could become endemic in wildlife. Similarly, there have been documented cases of household pets, including cats and dogs, contracting the virus from their owners. These animals developed antibodies, suggesting that they had mounted an immune response to the infection. This further underscores the importance of understanding the dynamics of cross-species transmission.
 
By identifying the RBD mutations that enhance the virus’s ability to infect animals, researchers hope to better anticipate potential zoonotic outbreaks and develop strategies to mitigate the risks. The study suggests that these mutations could lead to the emergence of new variants that are not only more infectious but also more capable of evading the immune responses of both humans and animals.
 
Deep Mutational Scanning and Viral Evolution
One of the key tools used in this study was deep mutational scanning (DMS), a technique that allows scientists to analyze the effects of thousands of mutations on viral proteins. DMS has proven invaluable in studying SARS-CoV-2 because it provides a detailed understanding of how mutations affect the virus’s ability to bind to ACE2 receptors and evade immune responses.
 
The researchers combined DMS data with topological deep learning (TDL), a cutting-edge approach that uses topological fingerprints to predict how mutations will affect protein function. By integrating these techniques, the team was able to create a model that accurately predicts how SARS-CoV-2 mutations will impact viral transmission across species. This could provide a valuable tool for forecasting the evolution of the virus and for designing vaccines and treatments that target future variants.
 
The MT-TopLap model, which was pre-trained on multiple DMS datasets, was able to predict the BFE changes caused by RBD mutations in various species. This allowed the researchers to pinpoint mutations that could enhance human-animal transmission and potentially lead to the emergence of new, more dangerous variants.
 
Conclusion: A Call for Vigilance and Further Research
The findings of this study highlight the ongoing need for vigilance in monitoring SARS-CoV-2 mutations and their potential to facilitate cross-species transmission. The mutations Q498H and R493K, in particular, pose a risk of enhancing the virus’s ability to jump between humans and animals, potentially leading to new outbreaks and complicating efforts to control the pandemic.
 
As the virus continues to evolve, it is crucial that scientists and public health officials remain alert to the possibility of new variants emerging from animal populations. By studying how these mutations affect viral transmission, researchers can develop more effective strategies for preventing and mitigating future zoonotic outbreaks.
 
The study findings were published in the peer-reviewed journal: Computers in Biology and Medicine.
https://www.sciencedirect.com/science/article/abs/pii/S0010482524011867
 
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