What is it about?
COVID-19 is caused by the SARS-CoV-2 virus, which enters human cells by attaching to a molecule on the cell surface called ACE2. Just like our physical traits such as height and eye color, there can be small natural variations in this ACE2 molecule among different people. We wanted to find out if these small variations could change how well the virus attaches and if this could make some people more or less susceptible to the virus. So, we tested this theory by looking at several variations of ACE2 found in humans and measuring how strongly they can bind to the virus. What we found was interesting - some variations allowed the virus to bind more strongly, potentially increasing the risk of infection. Others made the virus bind less well, which could possibly provide some protection against the virus. Importantly, we noticed that some of these variations are more common in certain populations, which could potentially impact how COVID-19 spreads among those groups. While most of these variations are rare, a few occur in more than 1 in 1,000 individuals, so they might have an important role in how COVID-19 affects different people. Lastly, we used computer programs to predict what might happen with even more variations of ACE2 than we could test in the lab. These predictions could help us to identify people who might be at a higher or lower risk from COVID-19 in the future.
Featured Image
Photo by CDC on Unsplash
Why is it important?
Our study is unique as it offers new insights into how genetic variations in the ACE2 protein, the key human cell entry point for SARS-CoV-2, could influence the spread and severity of COVID-19 among different populations. While previous research has established the role of ACE2 in SARS-CoV-2 infection, our work takes it a step further by investigating how specific genetic variants could either enhance or inhibit the virus's ability to bind to ACE2, hence affecting the risk and course of the disease. What's more, we've discovered certain variants of ACE2 that are prevalent in specific population cohorts, such as the African, Ashkenazi Jewish, and European non-Finnish groups. This finding is critical, as it could potentially inform tailored public health strategies and interventions to combat COVID-19 more effectively in these specific populations. Our study's findings also have broader implications for the understanding and prediction of susceptibility to other diseases that use ACE2 or similar receptors for cell entry. By comparing our experimental results with computational predictions, we provide a foundation for future research to refine these methods and expand our capacity to assess potential genetic risk factors for infectious diseases like COVID-19. Ultimately, this could lead to more personalized preventive measures and treatments.
Perspectives
This research began during the first UK lockdown, an intense period marked by long work weeks exceeding 80 hours. During this time, I compiled the first set of predictions and drafted an initial preprint. I was thrilled by the reception from eLife reviewers, although it was disheartening when one reviewer felt our study didn't meet the novelty standards due to a similar topic covered in another preprint. This was quite a blow, considering the significant effort and sacrifices made, not only by me but by my family as well. However, such is the nature of scientific research - opinions vary, and editors must base their decisions on these varied viewpoints. While it felt like a setback at the time, this led to a fortuitous development. We initiated a collaboration with an experimental lab, which not only brought this paper to fruition but also led to another significant paper on Spike variants. In retrospect, the entire journey was a testament to the grit, resilience, and collaboration intrinsic to scientific research, especially in response to global health emergencies. It reinforced the idea that progress sometimes comes from unexpected directions, and it was an honor to be a part of this endeavor, contributing to the ongoing battle against COVID-19.
Dr Stuart MacGowan
University of Dundee
Read the Original
This page is a summary of: Missense variants in human ACE2 strongly affect binding to SARS-CoV-2 Spike providing a mechanism for ACE2 mediated genetic risk in Covid-19: A case study in affinity predictions of interface variants, PLoS Computational Biology, March 2022, PLOS,
DOI: 10.1371/journal.pcbi.1009922.
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Resources
Affinity predictions of interface variants & ACE2 linked genetic risk in Covid-19 (ISMB Madison)
This presentation, originally delivered at the 3D-Sig section during the 30th Annual Intelligent Systems for Molecular Biology (ISMB) conference held in Madison in July 2022, provides a deep dive into the vital role of protein-protein interactions and genetic factors in understanding the pathology of COVID-19. The study centers around the analysis of interface variants and their affinity predictions, specifically focusing on their interactions with Angiotensin-Converting Enzyme 2 (ACE2), a key player in the SARS-CoV-2 infection process. This comprehensive examination offers invaluable insights into the complex relationship between viral binding, genetic variants, and their contribution to the individual risk of developing severe COVID-19. In addition to detailing the methodology and results of the research, the presentation also illustrates the applications of bioinformatics tools and computational modeling techniques in predicting protein-protein interactions. The findings presented have significant implications in understanding individual genetic risk for COVID-19, potentially guiding targeted interventions and personalized treatment strategies. As we continue grappling with the global COVID-19 pandemic, understanding the intricate web of interactions at the molecular level is essential. This presentation is an important step in this direction, contributing to our collective knowledge about this devastating disease.
Increased infectiousness of coronavirus variants explained
Researchers from the Universities of Dundee and Oxford have made a discovery that helps explain why variations in the virus that causes Covid-19 spread so rapidly.
Missense variants in ACE2 affect SARS-CoV-2 Spike binding and could contribute to genetic risk in Covid-19 - Poster at ISMB Madison 2022
This poster, presented at ISMB 2022 in Madison in the 3D-Sig COSI, explores the influence of ACE2 variants on the binding of the SARS-CoV-2 Spike protein, thereby impacting the susceptibility to Covid-19. It showcases the findings on how certain ACE2 alleles exhibit inhibited binding to Spike, while others show moderately increased affinity. By comparing our results to recent infectivity studies, we hypothesize that the affinity ranges of ACE2 variants can protect cells from infection, which suggests that certain alleles might confer resistance to their carriers. This is currently being tested with clinical data. The poster also examines the strengths and limitations of current predictive models, and presents new findings on the interaction between ACE2 variants and different strains of SARS-CoV-2.
Contributors
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