Common genetic variants involved in mediating asymptomatic transmission of SARS-CoV-2

Have you ever wondered why some people didn’t get sick from COVID-19? A study released today found that Nature We show that a common genetic variation among people is responsible for mediating asymptomatic transmission of SARS-CoV-2. The results show that people with this mutation do not feel sick once infected. This exciting discovery was the result of a US-Australia collaboration led by Dr. Danilo Augusto, an assistant professor at the University of North Carolina at Charlotte. Dr. Jill Hollenbach, Professor, University of California, San Francisco. Stephanie Gras, professor at La Trobe University, Australia.

This research focuses on a group of genes called human leukocyte antigens (HLA). These HLA genes encode proteins that the immune system uses to identify healthy cells and distinguish them from cells infected with bacteria or viruses. The HLA system is critical for immune responses, but varies greatly between individuals. Because of her HLA’s role in fighting infectious diseases, researchers wondered if there might be certain variants that make us more protective or susceptible to the SARS-CoV-2 virus.

Hollenbach led the data collection that began early in the pandemic. First, 29,947 unvaccinated people were screened using a mobile app specifically designed to track COVID-19 symptoms, and 1,428 reported testing positive for the virus. All individuals had previously had her DNA sequenced to analyze HLA genes. Researchers found that people with the HLA-B*15:01 mutation were much more likely to remain asymptomatic after infection. Remarkably, this variant is present in approximately 10% of the population. In summary, people with her HLA-B*1501 in their genome did not avoid infection, but did not get sick.

We hypothesized that their immune system reacts so quickly and so strongly that the virus is eliminated before it causes symptoms. It’s like having an army that already knows what to look for and just by looking at their uniforms you can tell they’re bad guys. ”

Dr. Jill Hollenbach, Professor, University of California, San Francisco

HLA molecules present parts of the virus to immune effector cells for inspection. The study used cells from an individual with HLA-B*15:01 who donated blood several years before the pandemic. The results showed that these people had memory T cells for specific particles of SARS-CoV-2. People who had never been in contact with SARS-CoV-2 had already been exposed in some way to other viruses and had developed immune memory to particles from SARS-CoV-2. Their immunological memory would elicit a much quicker response, explaining why those people remain asymptomatic. Yet it was still of interest how they could develop immune memory against SARS-CoV-2 without ever being exposed to the virus.

“It’s widely known that other types of coronaviruses have caused seasonal colds for decades. We hypothesized that these people had been exposed to seasonal coronaviruses in the past, and that somehow people who specifically harbored HLA-B*15:01 could quickly kill cells infected with SARS-CoV-2 through a cross-reactive immune response. Thus, even if the bad guys changed their uniforms, the military would still have tattoos on their boots and arms.” That’s how our immunological memory works to keep us healthy,” Augusto said.

After careful analysis of the genome sequences of all coronaviruses, this study showed that this SARS-CoV-2 particle recognized by HLA-B*15:01 in unexposed individuals is highly similar to virions of other previous coronaviruses. By presenting crystal structures and affinity assays, this study demonstrated that pre-pandemic individual T cells were able to discriminate past coronavirus and SARS-CoV-2 virus particles with the same efficiency. This means that these individuals have created immunological memories against previous coronaviruses, but the high similarity of this viral particle also allows memory T cells to recognize and kill SARS-CoV-2 very quickly.

The results provide a mechanism for how individuals can avoid illness from SARS-CoV-2, and the research group will continue to learn about their response to the virus, which will lead to a better understanding of COVID-19 treatments and vaccines.