Nature has recently uncovered the genetic mystery of "why some people never show symptoms of COVID-19"!

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New research suggests that common genetic variations between people regulate asymptomatic SARS-CoV-2 infections.

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Have you ever wondered why some people never get sick from COVID-19? A recent study published in the journal Nature suggests that a common genetic variant among humans is responsible for mediating SARS-CoV-2 asymptomatic infections. The results show that individuals carrying this variant do not feel sick once infected. This exciting discovery is the result of a collaboration between the United States and Australia, led by Dr Danillo Augusto, Assistant Professor at the University of North Carolina at Charlotte; Dr Jill Hollenbach, Professor at the University of California, San Francisco; and Stephanie Gras, Professor at La Trobe University, Australia.

The role of human leukocyte antigens (HLA)

This study focused on a group of genes known as human leukocyte antigens (HLA). These HLA genes code for proteins that are used by the immune system to recognize your healthy cells and distinguish them from cells infected by bacteria and viruses. The HLA system is crucial to the immune response and is highly variable between individuals. Because of HLA's role in fighting infections, the researchers wanted to know if there were specific variants that would make us more protected or more susceptible to the SARS-CoV-2 virus.

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Findings and Methods

Hollenbach led data collection efforts that began at the start of the pandemic. First, 29,947 unvaccinated people were screened using a mobile app specifically designed to track COVID-19 symptoms, of which 1,428 reported testing positive for the virus. All had previously had their DNA sequenced to analyze their HLA genes. The researchers found that individuals carrying the HLA-B*15:01 gene variant were more likely to remain asymptomatic after infection. Impressively, this variant is present in about 10 percent of the population. In short, individuals with HLA-B*1501 in their genomes were not immune to infection, however, they did not become ill.

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Insights into the immune response

"We hypothesize that their immune system responded so quickly that the virus was eliminated before it caused any symptoms. It's like having an army that already knows what to look for and can tell by the uniforms that these are the bad guys," Hollenbach said.

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The HLA molecules present viral fragments to immune effector cells for examination. The cells used in the study came from HLA-B*15:01 patients who donated their blood several years before the flu pandemic. The results showed that these individuals had memory T cells that targeted specific particles of SARS-CoV-2. Individuals who had never been exposed to SARS-CoV-2 had been previously exposed to other viruses and had developed an immune memory for SARS-CoV-2 particles.

Their immune memory triggered a faster response, which explains why these people were asymptomatic. Nonetheless, it remains interesting to see how they were able to develop an immune memory against SARS-CoV-2 without having been exposed to the virus.

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Cross-reactive immune response

"It is well known that other types of coronaviruses have caused seasonal colds for decades. We hypothesize that these individuals were exposed to seasonal coronaviruses in the past and that individuals specifically carrying HLA-B*15:01 can quickly kill SARS-CoV-2 infected cells due to cross-reactive immune responses. So even if the bad guys change uniforms, the military can still recognize them by their boots or the tattoos on their arms. This is how our immune memory keeps us healthy," Augusto says. ???????????????

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After carefully analyzing the genome sequences of all coronaviruses, the study showed that in unexposed individuals, this SARS-CoV-2 particle recognized by HLA-B*15:01 is very similar to viral particles from other previous coronaviruses. It was shown that T cells from pre-pandemic individuals could recognize viral particles from past coronaviruses and SARS-CoV-2 with the same efficiency by displaying crystal structure and affinity analysis. This means that these individuals had developed an immune memory for previous coronaviruses, but due to the high similarity of such viral particles, their memory T-cells could also quickly recognize and kill SARS-CoV-2.

Takeaways and Future Research

The findings show the mechanisms of how individuals avoid getting sick from SARS-CoV-2, and the team plans to continue to learn about the response to this virus, which will help to better understand COVID-19 treatments and vaccines.

A common allele of HLA is associated with asymptomatic SARS-CoV-2 infection