People who get COVID-19 but never develop symptoms, called super dodgers, may have a hereditary advantage. According to a new study led by researchers at UC San Francisco, they are more than twice as likely as individuals who become symptomatic to harbor a specific genetic variation that aids in the eradication of the virus.
The paper, published July 19, 2023 in Nature, offers the first evidence that there is a genetic basis for asymptomatic SARS-CoV-2. The research is helping to solve the mystery of why some people can be infected but never get sick from COVID-19.
The secret lies in human leukocyte antigen (HLA), or protein markers that signal the immune system. A mutation in one of the genes coding for HLA appears to help virus-killing T cells identify SARS-CoV-2 and launch a lightning attack.
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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. This discovery indicates new targets for drugs and vaccines.
“If you have an army that can recognize the enemy early, that’s a huge advantage,” explained the study’s lead researcher, Jill Hollenbach, PhD, MPH, professor of neurology, as well as epidemiology and biostatistics, and fellow of the Weill Institute for Neuroscience at UCSF. “It’s like having soldiers who are prepared for battle and already know what to look for, and they’re the bad guys.”
The mutation – HLA-B15:01 – is quite common, carried by around 10% of the study population. This does not prevent the virus from infecting cells, but rather prevents people from developing symptoms. This includes a runny nose or even a barely noticeable sore throat.
The UCSF researchers found that 20% of people in the study who remained asymptomatic after infection carried 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 significantly more likely – more than eight times – to avoid feeling sick.
Leveraging a National Marrow Donor Database
The researchers suspected early on that HLA was involved, and luckily there was a national registry with the data they were looking for. The National Marrow Donor Program/Be The Match, the largest voluntary HLA donor registry in the United States, matches donors with people in need of a bone marrow transplant.
But they still needed to know how donors were coping with 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 were followed through the first year of the pandemic. At that time, vaccines were not yet available, and many people were getting routine COVID testing for work or whenever they were potentially exposed.
“We didn’t set out to study genetics, but we were thrilled to see this result come 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 primary study group was limited to those who identified as white because the final set of study respondents did not include enough people from other ethnic and racial groups to analyze.
The researchers identified 1,428 unvaccinated donors who tested positive between February 2020 and the end of April 2021, before vaccines became widely available and it still took several days to get test results.
Of these, 136 people remained asymptomatic for at least two weeks before and after testing positive. Only one of the HLA variants – HLA-B15:01 – 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 conditions like diabetes, did not appear to play a role in remaining asymptomatic.
“We are proud to partner with research that has the potential to leverage long-term public investment in the creation of the national registry to help cure diseases and improve our ability to prevent future pandemics,” said Martin Maiers, vice president of research at the National Marrow Donor Program/Be The Match.
To understand how HLA-B15 managed to crush 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 examined T cells from people who had 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 novel coronavirus called the NQK-Q8 peptide. They concluded that exposure to certain seasonal coronaviruses, which have a very similar peptide, called NQK-A8, allowed the T cells of these individuals to quickly recognize SARS-CoV-2 and mount a faster and more rapid immune response. more efficient.
“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 Professor Stephanie Gras. and head of laboratory at La Trobe University.