A common variant in an immune system HLA gene (HLA-B*15:01) has been linked to a higher chance of avoiding symptoms after SARS-CoV-2 infection.
At least 20% of people infected with SARS-CoV-2 coronavirus never feel sick. Now, scientists have identified an allele of the HLA system (containing genes that control the immune response) that is associated with a greater likelihood of avoiding symptoms during infection (Augusto, DG et al., Nature https:// doi.org/10.1038/s41586-023-06331-x (2023)).
This HLA allele (HLA-B*15:01) appears to confer an advantage on the immune cells of people who have been previously exposed to the “seasonal” coronavirus that causes the common cold. This extra boost means the immune system can fast track and eliminate SARS-CoV-2 before it becomes rampant and dysregulated and tries to defend itself against the virus.
The study “deserves applause”, with the researchers showing that the link to COVID-19 is “stronger than any other common genetic association that has been published”.
Much of the research exploring the link between genetics and COVID-19 risk has focused on how it can lead to severe illness or death. These are important studies, but most people infected with SARS-CoV-2 have mild clinical disease.
To detect asymptomatic infections, the authors used a bone marrow donor database and recruited nearly 30,000 individuals. Participants reported any positive test results for SARS-CoV-2 and any symptoms. Of more than 1,400 participants who tested positive for the 15-month study, which was conducted before the vaccine was widely available, 136 remained asymptomatic.
The researchers then looked for a link between recessive infection and variations in the HLA gene, which encodes a protein that is found on the surface of nearly every cell in the body. These proteins display fragments of potential immune system invaders, triggering immune defenders called T cells to take action 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 allele were twice as likely to remain asymptomatic than those without the allele; people with two copies of the gene were eight times more likely than others. The extent to which HLA alleles (HLA-B*15:01) contribute to the minimal clinical response to SARS-CoV-2 is surprising.
The researchers primarily analyzed participants who identified themselves as white because they did not have enough other ethnic groups to analyze. The authors also found evidence of this link in blacks, but the results were less clear in Asians and Hispanics.
BYT cells of the immune system have memory
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 collected from people with the protective variant before the pandemic. Since these cells have never been exposed to SARS-CoV-2, they have no “memory” of the virus. Still, when the protein (HLA-B*15:01) presented T cells with fragments of the SARS-CoV-2 “spike” protein, the T cells continued to mount the attack.
This fragment is structurally similar to the seasonal coronavirus-driven spike protein fragment. This similarity may allow T cells previously exposed to the common cold coronavirus to recognize SARS-CoV-2 and mount an immune response faster than unexposed cells.
How cytotoxic T cells boost immunity against novel coronavirus variants.
Scientists speculate that the HLA protein (HLA-B*15:01) is better and more efficient at displaying fragments of the SARS-CoV-2 spike protein than other HLA variants, in a way that does become more like seasonal coronavirus virus, which can stimulate a stronger anti-coronavirus immune response.
The results could help vaccinologists develop next-generation COVID-19 vaccines that not only manage the severity of the disease but also prevent symptoms.
The HLA complex system contains genes that control the immune response to infectious agents, malignant cells, infection, or normal cells altered by chemical exposure. This explains why people with certain HLA genes react strongly to the hepatitis B virus and develop severe acute liver failure, while those without these HLA genes (alleles) have subclinical or mild infection . Also, certain genes (alleles) of the HLA system predispose you to autoimmune diseases, for example HLD-DR3/4 predisposes one to Hashimoto’s thyroiditis, lupus and rheumatoid arthritis; HLA-B27 predisposes one to more Predisposition to ankylosing spondylitis or reactive arthritis secondary to inflammatory bowel disease or psoriasis, to name a few. Conversely, people with HLA alleles that protect against certain infections can make people very susceptible to serious diseases, such as in Africa, where people with sickle cell disease are much more resistant to malaria.
Ronald Palacios Castrillo, MD, Ph.D.