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COVID-19 Resistance

The Search for Natural COVID-19 Resistance
    
    As of November 2021, 249 million people have been infected with COVID-19 across the globe. Although much progress has been made in understanding the coronavirus since December 2019, there is still a lot that is unknown. Just like any other infection, each COVID-19 infected individual reacts very differently to the virus; some are asymptomatic, some have mild symptoms and recover without treatment, some are hospitalized with severe acute respiratory syndrome, and some die. In rare cases, there have been people who were exposed without protection to COVID-19 over an extended period of time and did not test positive. These clinical variabilities can be explained by human genetic factors- it’s possible that some lucky individuals have inborn resistance to COVID infection.

    Looking back in history, this type of mechanism has previously been observed with HIV, the virus behind AIDS. Through genetic studies on people who were resistant to HIV infection, scientists discovered that the autosomal recessive CCR5 deficiency confers resistance to HIV infection. The CCR5 protein is required for HIV enter human cells. If a genome contains a loss of function mutation in CCR5, an individual will not get HIV infection. Based on the genetic mechanism, scientists developed a drug to target CCR5 and CCR5 deficient bone marrow transplantation to treat and cure HIV infection. Scientists hope to use similar genetic strategies to serve as a guide to find specific treatments for COVID-19.

What's known so far

    Since the beginning of the pandemic, scientists have been working hard to understand SARS-CoV-2 infection. Several candidate resistance genes have emerged from lines of genomic studies, one being the ABO blood group. A recent meta-analysis of nearly 50,000 people from 46 studies confirmed the effects of the ABO locus on susceptibility to infection. The data indicates that there is a protective effect of the O allele. 

    Additionally, it was discovered early on in the pandemic that SARS-CoV-2 infection is dependent on the ACE2 receptor for cell entry. Through genome-wide association studies, a rare variant located close to ACE2 was found to confer protection against SARS-CoV-2 infection, possibly by decreasing ACE2 expression and thus reducing viral entry to cells. Scientists are still conducting more genome-wide screening, hoping to find the required gene to permit infection with the virus.

Searching for COVID-19 resistant individuals

    A group of scientists led by Dr. Jean-Laurent Casanova from The Rockefeller University and Dr. Helen Su from National Institute of Allergy and Infectious Disease have launched a global hunt for people who are genetically resistant to COVID-19 infection (http://www.covidhge.com). The scientists are applying a four-step strategy to overcome uncertainties about COVID-19 exposure in the search for monogenic inborn variants of immunity to SARS-CoV-2 infection:
  1. Identify uninfected household contacts of people with symptomatic COVID-19
  2. Consider individuals with prolonged exposure to COVID-19 without protection equipment
  3. Enroll individuals with negative PCR and serology results
  4. Assess SARS-CoV-2 specific T-cell responses in candidate resistant individuals and compare with infected individuals
    Once an individual passes all of these qualifications, their sample will be analyzed by whole-exome/genome sequencing to identify rare or common variants with a strong effect on resistance to infection. So far, researchers have already enrolled over 400 individuals who meet the criteria for inclusion and the enrollment is still ongoing.

Implications

    Historical examples of inborn resistance to infection with other pathogens provide a road map for testing the hypothesis of monogenic inborn resistance to infection with SARS-CoV-2. The finding of these resistant variants is significant not only because they will provide a deeper understanding of the essential biological pathways involved in SARS-CoV-2 infection, but also because they will provide critical insight for the development of innovative therapeutic interventions to prevent or treat SARS-CoV-2 infection.

Sources

1. Andreakos, Evangelos, et al. “A Global Effort to Dissect the Human Genetic Basis of Resistance to SARS-COV-2 Infection.” Nature Immunology, 18 Oct. 2021, https://doi.org/10.1038/s41590-021-01030-z.

2. Covid Human Genetic Effort. http://www.covidhge.com/.

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