People who contract COVID-19 but never develop symptoms, so-called super-dodgers , may have a genetic ace up their sleeve. They are more than twice as likely as those who become symptomatic to carry a specific genetic variation that helps them clear the virus, according to a new study led by UC San Francisco researchers.
The paper, published in Nature , offers the first evidence that there is a genetic basis for asymptomatic SARS-CoV-2. The research helps solve the mystery of why some people can be infected without getting sick from COVID-19.
The secret is in the human leukocyte antigen (HLA), or protein markers that signal the immune system. A mutation in one of the genes that code for HLA appears to help virus-killing T cells identify SARS-CoV-2 and launch a lightning attack. The T cells of some people who carry this variant can identify the new coronavirus, even if they have never encountered it before, thanks to its resemblance to the seasonal cold viruses they already know. The discovery points to new targets for drugs and vaccines.
"If you have a military that can recognize the enemy early, that’s a huge advantage," explained the study’s principal investigator, Jill Hollenbach, PhD, MPH, professor of neurology, as well as epidemiology and biostatistics, and a member of the Weill Institute for Neurosciences. from UCSF. "It’s like having soldiers who are prepared for battle and who already know what to look for, and that these are the bad guys."
The mutation, HLA-B*15:01, is quite common and is carried by about 10% of the study population. It doesn’t prevent the virus from infecting cells, but rather it prevents people from developing any symptoms. That includes a runny nose or even a barely noticeable sore throat.
UCSF researchers found that 20% of people in the study who remained asymptomatic after infection had at least one copy of the HLA-B*15:01 variant, compared to 9% of those who reported symptoms . Those who carried two copies of the variant were much more likely, more than eight times, to avoid feeling sick.
Leveraging a national marrow donor database
Researchers suspected from the beginning that HLA was involved, and fortunately, a national registry existed that contained the data they were looking for. The National Marrow Donor Program/Be The Match, the largest registry of HLA-typed voluntary donors in the U.S., matches donors with people in need of bone marrow transplants.
But they still needed to know how donors fared against COVID-19. So, they turned to a mobile app developed at UCSF, called the COVID-19 Citizen Science Study. They recruited nearly 30,000 people who were also on the bone marrow registry and tracked them during the first year of the pandemic. At the time, vaccines were not yet available and many people were undergoing routine COVID testing for work or when potentially exposed.
"We didn’t set out to study genetics, but we were excited to see this result coming from our multidisciplinary collaboration with Dr. Hollenbach and the National Marrow Donor Program," said Mark Pletcher, MD, MPH, professor of epidemiology and biostatistics at UCSF. .
The main study group was limited to those who self-identified as white because the study’s final group of respondents did not have enough people from other racial and ethnic groups to analyze.
Researchers identified 1,428 unvaccinated donors who tested positive between February 2020 and late April 2021, before vaccines were widely available and when it still took many days to get test results.
Of these, 136 individuals remained asymptomatic for at least two weeks before and after testing positive. Only one of the HLA variants, HLA-B*15:01, had a strong association with asymptomatic COVID-19 infection, and this was replicated in two independent cohorts. Risk factors for severe COVID-19, such as being older, overweight and having chronic diseases such as diabetes, did not appear to influence those who remained asymptomatic.
"We are proud to partner on research that has the potential to leverage a long-term public investment in building the national registry to help cure diseases and improve our ability to prevent future pandemics," said Martin Maiers, vice president of research at National Bone Marrow Donation Program/Be The Match.
To find out how HLA-B15 managed to nullify the virus, Hollenbach’s team collaborated with researchers at La Trobe University in Australia. They focused on the concept of T cell memory, which is how the immune system remembers previous infections.
The researchers looked at T cells from people who carried HLA-B15 but had never been exposed to the SARS-CoV-2 virus and found that these cells still responded to a part of the new coronavirus called the NQK-Q8 peptide. They concluded that exposure to some seasonal coronaviruses, which have a very similar peptide, called NQK-A8, allowed T cells in these individuals to quickly recognize SARS-CoV-2 and mount a faster and more effective immune response.
"By studying their immune response, this could allow us to identify new ways to promote immune protection against SARS-CoV-2 that could be used in future vaccine or drug development," said Stephanie Gras, professor and laboratory head at La Trobe. . University.
