Have you had Covid but no symptoms? You may have an allele (HLA-B*15:01) of the HLA system of immune response genes

A common variant of the HLA gene (HLA-B*15:01) in the immune system is associated with a higher chance of surviving symptoms after SARS-CoV-2 infection.

At least 20% of people infected with the SARS-CoV-2 coronavirus never feel sick. Now, scientists have identified an allele of the HLA system (contains genes that control the immune response) that is related to a greater likelihood of surviving symptoms during infection (Augusto, DeG et al. Nature https:/ https://doi.org/10.1038/s41586-023-06331-x (2023).

This HLA allele (HLA-B*15:01) benefits the immune cells of people who have previously been exposed to “seasonal” coronaviruses that cause the common cold. That extra boost means the immune system can rapidly detect and destroy SARS-CoV-2 before it becomes unruly and disorganized in trying to defend itself against the virus.

The study “deserves praise”, the researchers said, for showing a “stronger” link to COVID-19 than any other published association for a common gene.

lucky people

Many studies exploring the link between genetics and COVID-19 risk have focused on how it leads to severe disease or death. These are important studies, but most people infected with SARS-CoV-2 have a mild clinical picture of the disease.

To find people with asymptomatic infection, the authors used a database of bone marrow donors and enrolled nearly 30,000 people. Participants self-reported any positive test for SARS-CoV-2 and any symptoms. Of the more than 1,400 participants who tested positive during the 15-month study, which was conducted before the vaccines were widely available, 136 remained asymptomatic.

The researchers then looked for a link between people who had the silent infection and variations in HLA genes, which code for proteins found on the surfaces of nearly every cell in the body. The proteins display fragments of potential immune system invaders, prompting immune defenders called T cells to act against the invaders.

The authors found an association between asymptomatic infection and the HLA allele (HLA-B*15:01) carried by approximately 10% of the study population. People with the gene allele were twice as likely to remain asymptomatic than those without it; It was eight times more likely in people with two copies of the gene. The magnitude of the effect of the HLA allele gene (HLA-B*15:01) on the minimal clinical response against SARSCoV-2 is surprising.

The researchers conducted the main analysis on participants who described themselves as white, as they did not have enough people from other ethnic groups to analyse. The authors also found evidence for an association in black people, but the results are less clear in Asian and Hispanic people.

BYT cells of the immune system remember

To understand how the variant (HLA-B*15:01) helps prevent symptoms, the authors focused on its interaction with T cells. The team obtained T cells that had been collected before the pandemic from people who had the protective variant. Because the cells had never been exposed to SARS-CoV-2, they had no “memory” of the virus. Nevertheless, the T cells went on the attack when the protein (HLA-B*15:01) presented them with a fragment of the SARS-CoV-2 “spike” protein.

This fragment is structurally similar to fragments of the spike protein that drives the seasonal coronavirus. This similarity may allow T cells previously exposed to the common cold coronavirus to recognize and develop an immune response to SARS-CoV-2 more quickly than unexposed cells.

How cytotoxic T cells can boost COVID immunity against the new variant.

The scientists believe that, compared to other HLA variants, the HLA protein (HLA-B*15:01) is better and more efficient at displaying the SARS-CoV-2 spike protein fragment in such a way that it binds to fragments. becomes like Seasonal coronavirus, which provokes a strong anti-coronavirus immune response.

The results could help vaccinologists develop next-generation COVID-19 vaccines that not only control the severity of the disease, but also prevent symptoms.

The HLA complex system contains genes that direct immune responses when altered by infectious agents, malignant cells, infected normal cells, or chemical exposure. This explains why people with certain HLA genes mount a strong response against hepatitis B virus and develop severe acute liver failure, while people without those HLA genes (alleles) have subclinical or mild infection. In addition, there are genes (alleles) of the HLA system that make you susceptible to autoimmune diseases, for example HLD-DR3/4 makes a person susceptible to Hashimoto’s thyroiditis, lupus and rheumatoid arthritis; HLA-B27 makes a person more likely to have inflammatory bowel disease or psoriasis followed by ankylosing spondylitis or reactive arthritis, and there are many examples of this. Conversely, people who have an HLA allele that protects against a certain infection can make a person more susceptible to severe forms of the disease, for example people with sickle cell disease in Africa are more resistant to malaria.

Ronald Palacios Castrillo, MD, Ph.D.

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