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  • A recent review summarizes current evidence about the role of genetic factors in a person’s response to SARS-CoV-2 infection.
  • People with certain gene variants, especially those that code for proteins involved in the immune response to SARS-CoV-2, may be more susceptible to severe COVID-19.
  • Variants of human genes that encode proteins that are necessary for supporting various stages of the virus’s life cycle could confer natural resistance to SARS-CoV-2 infection.
  • Identifying gene variants that confer this resistance may help scientists develop treatments for COVID-19.

SARS-CoV-2 is highly likely to transmit from one person to the members of their household.

One 2020 review suggests that on average, the likelihood of SARS-CoV-2 transmitting to household contacts is 16.9%. But this increases to 41.5% in households made up of the person with the infection and one other contact.

Yet some people do not develop the infection even after prolonged contact with household members who have it. This suggests that these people may be resistant to SARS-CoV-2 infection.

Genetic factors are known to play a significant role in determining response to infectious disease.

A recent review published in Nature Immunology summarizes current evidence about genetic factors that could explain the variability in individual response to SARS-CoV-2 infection. Specifically, it describes genes that may result in increased susceptibility to SARS-CoV-2 and those that could potentially confer resistance.

The review was authored by researchers participating in the COVID Human Genetic Effort, an international collaboration that aims to understand the genetic and immune factors underlying SARS-CoV-2 infection.

Paul Bastard, a doctoral student at Imagine Institute, in Paris, and a collaborator in the COVID Human Genetic Effort, explained the significance of identifying genes that may confer natural resistance against SARS-CoV-2 to Medical News Today:

“This would be of major importance, as it could help identify the pathways involved in the fight against COVID-19. It could help us better understand the pathogenesis of COVID-19. In addition, it could potentially lead to the development of new therapeutics.”

Previous studies have shown that possessing certain genetic variants can increase susceptibility to tuberculosis. These genes generally encode proteins that are involved in the immune response.

Similarly, scientists have found mutations in genes that are involved in or influence the type-1 interferon response in people with severe COVID-19. Type-1 interferons are important chemical messengers in the immune system and are crucial to our antiviral response.

Certain gene variants can also, however, protect a person from severe illness and even confer resistance to an infectious disease.

For instance, people with a mutation in the gene that encodes the CCR5 receptor are naturally resistant to HIV-1. The CCR5 receptor binds to chemokines, a family of immune proteins, and is used by HIV-1 to enter human cells and spread in the body. People with a CCR5 gene mutation express a shorter version of the CCR5 protein, preventing HIV from entering and infecting cells.

The discovery of this natural resistance led to the development of drugs that block the receptor. This example shows how characterizing genes that confer natural resistance can facilitate the development of treatments for infectious diseases.

Likewise, scientists have identified several candidate genes that could potentially confer resistance against SARS-CoV-2 infection.

SARS-CoV-2 enters human cells by binding to the angiotensin-converting enzyme 2 (ACE2) protein, which is expressed on the surface of a wide variety of cells.

A recent preprint study, which has yet to be peer reviewed, showed that a rare gene variant located close to the ACE2 gene is associated with a lower risk of SARS-CoV-2 infection and severe illness.

Moreover, the study suggests that these protective effects may result from the variant gene’s ability to reduce ACE2 expression and, thus, potentially influence the entry of SARS-CoV-2.

Other laboratory studies have identified human proteins that interact with SARS-CoV-2 and facilitate processes essential for viral infection. Variants of these genes could thus potentially confer resistance to SARS-CoV-2.

The characterization of genes that confer resistance to SARS-CoV-2 requires the identification of individuals with a natural resistance to the infection. However, there are a few major methodological obstacles.

One is demonstrating that a person has contracted SARS-CoV-2 in the past. Polymerase chain reaction (PCR) tests using nasal swabs or other respiratory samples only provide information about recent exposure to the virus. While detecting antibodies in plasma samples can provide information about a prior SARS-CoV-2 infection, a small percentage of individuals who have had the infection do not have detectable levels of antibodies.

It can also be challenging to distinguish individuals who have never been exposed to the virus from those who possess natural resistance.

The authors of the Nature Immunology review are currently conducting a study to characterize genes that may confer resistance to SARS-CoV-2 infection and propose a strategy to address these challenges.

To identify people with natural resistance to SARS-CoV-2 infection, the authors intend to enroll participants who do not have the infection but have a household member, especially a spouse or partner, with symptomatic COVID-19.

They also intend to include people without the infection who have been in contact, without protective equipment, with a symptomatic person during the first 3–5 days of their infection.

And in addition to PCR and antibody testing, they propose to assess the participants’ T-cell responses.

The immune response to a SARS-CoV-2 infection is characterized by the production of antibodies and a response by T cells, a type of white blood cell. The absence of a T-cell response specific to the virus, along with negative PCR and antibody tests, could thus help confirm the absence of a prior SARS-CoV-2 infection.

After analyzing the genomes of these participants to identify genes associated with natural resistance to SARS-CoV-2 infection, the authors will conduct subsequent studies to determine the role of the genes in the infection process.

Dr. Nikolai Klebanov, of the Harvard Dermatology Residency Program, in Boston, told MNT:

“Studying host genetic predisposition for susceptibility or resistance to COVID-19, through genome-wide association studies or whole exome or genome sequencing, could uncover potential viral entry points and key pathways of immune resistance to the virus. This could allow for the development of new, targeted drugs or vaccines for COVID-19, as well as to better risk-stratify vulnerable populations.”

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