There’s a good reason why some people who contract Covid-19 never develop symptoms, according to a recent study, which suggests these so-called “super dodgers” may hold a genetic ace – being more than twice as likely as those who become symptomatic to carry a specific gene variation that helps them obliterate the virus.
The findings, by a team from the University of California-San Francisco and published in Nature, offer the first evidence yet that there is a genetic basis for asymptomatic SARS-CoV-2, and helps to solve the mystery of why some people can be infected without ever getting sick from Covid-19.
The secret lies with the 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 lighting attack. The T cells of some people who carry this variant can identify the novel 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 an army that’s able to recognise the enemy early, that’s a huge advantage,” said lead researcher Jill Hollenbach, professor of neurology as well as epidemiology and biostatistics, and a member of the Weill Institute for Neurosciences at UCSF.
The mutation – HLA-B*15:01 – is quite common, carried by about 10% of the study’s population. It doesn’t prevent the virus from infecting cells but, rather, 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 carried at least one copy of the HLA-B*15:01 variant, compared with 9% of those who reported symptoms. Those who carried two copies of the variant were far more likely – more than eight times – to avoid feeling sick.
Leveraging a national marrow donor database
Researchers suspected early on that HLA was involved, and fortunately a national registry existed that contained the data they were looking for. The National Marrow Donor Programme/Be The Match, the largest registry of HLA-typed volunteer donors in the US, matches donors with people needing bone marrow transplants.
But they still needed to know how the 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 in the bone marrow registry and tracked through the first year of the pandemic.
At that time, vaccines were not yet available, and many people were undergoing routine Covid testing for work or whenever they were potentially exposed.
“We did not set out to study genetics, but were thrilled to see this result come from our multidisciplinary collaboration,” said Dr Mark Pletcher, a professor of epidemiology and biostatistics at UCSF.
Researchers identified 1 428 unvaccinated donors who tested positive between February 2020 and the end of April 2021, before the vaccines were widely available and when it still took many days to get back 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 reproduced in two independent cohorts.
Risk factors for severe Covid-19, like being older, overweight and having chronic diseases like diabetes, did not appear to play a role in who remained asymptomatic.
To figure out how HLA-B15 managed to quash the virus, Hollenbach’s team collaborated with researchers from La Trobe University in Australia. They homed in 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 these cells still responded to a part of the novel coronavirus called the NQK-Q8 peptide. They concluded that exposure to some seasonal coronaviruses, which have a very similar peptide, called NQK-A8, enabled T cells in these individuals to quickly recognise SARS-CoV-2 and mount a faster, more effective immune response.
“By studying their immune response, this might enable us to identify new ways of promoting immune protection against SARS-CoV-2 that could be used in future development of vaccine or drugs,” said Stephanie Gras, a professor and laboratory head at La Trobe University.
Study details
A common allele of HLA is associated with asymptomatic SARS-CoV-2 infection
Augusto, DG, Murdolo, LD, Chatzileontiadou, D., et al.
Published in Nature on 19 July 2023
Abstract
Studies have demonstrated that at least 20% of individuals infected with SARS-CoV-2 remain asymptomatic. Although most global efforts have focused on severe illness in Covid-19, examining asymptomatic infection provides a unique opportunity to consider early immunological features that promote rapid viral clearance. Here, postulating that variation in the human leukocyte antigen (HLA) loci may underly processes mediating asymptomatic infection, we enrolled 29,947 individuals, for whom high-resolution HLA genotyping data were available, in a smartphone-based study designed to track Covid-19 symptoms and outcomes. Our discovery cohort (n = 1,428) comprised unvaccinated individuals who reported a positive test result for SARS-CoV-2. We tested for association of five HLA loci with disease course and identified a strong association between HLA-B*15:01 and asymptomatic infection, observed in two independent cohorts. Suggesting that this genetic association is due to pre-existing T cell immunity, we show that T cells from pre-pandemic samples from individuals carrying HLA-B*15:01 were reactive to the immunodominant SARS-CoV-2 S-derived peptide NQKLIANQF. The majority of the reactive T cells displayed a memory phenotype, were highly polyfunctional and were cross-reactive to a peptide derived from seasonal coronaviruses. The crystal structure of HLA-B*15:01–peptide complexes demonstrates that the peptides NQKLIANQF and NQKLIANAF (from OC43-CoV and HKU1-CoV) share a similar ability to be stabilised and presented by HLA-B*15:01. Finally, we show that the structural similarity of the peptides underpins T cell cross-reactivity of high-affinity public T cell receptors, providing the molecular basis for HLA-B*15:01-mediated pre-existing immunity.
See more from MedicalBrief archives:
Up to 45% of Covid infections may be asymptomatic — Scripps analysis
‘Vast majority’ with COVID-19 are asymptomatic — UK’s Office of National Statistics
New T-cell therapy has potential to kill most human cancer types – animal study