Findings may help clinical laboratories identify healthcare workers who could work on the front lines of the next pandemic without fear of serious infection
University of California San Francisco researchers have discovered a gene mutation that enables some people’s immune system to recognize and respond to a COVID-19 infection despite having no prior exposure to the SARS-CoV-2 coronavirus (which would produce antibodies against future infections).
This genetic advantage will be of interest to clinical laboratory professionals and pathologists involved in immune system testing. Why some individuals with COVID-19 show few if any symptoms has confounded microbiologists and virologists since the beginning of the pandemic. Now, the UC San Francisco (UCSF) scientists believe they know why.
Dark Daily previously covered the UCSF study in “UCSF Researchers Identify Genetic Mutation That Promotes an Asymptomatic Response in Humans to COVID-19 Infection.” We covered how variations in a specific gene in a system of genes responsible for regulating the human immune system appears to be the factor in why about 10% of those who become infected with the virus are asymptomatic. And we predicted that understanding why some people display no symptoms during a COVID-19 infection could lead to new precision medicine genetic tests medical laboratories could use to identify people with the mutated gene.
The UCSF scientists published their latest findings in the journal Nature titled, “A Common Allele of HLA Is Associated with Asymptomatic SARS-CoV-2 Infection.”
“If you have an army that’s able to recognize the enemy early, that’s a huge advantage,” said immunogeneticist Jill Hollenbach, PhD, in a UCSF news release. Hollenbach led the research team that identified a mutated gene responsible for immune response to COVID-19 in individuals who have not been exposed to the SARS-CoV-2 coronavirus. Clinical laboratory professionals and pathologists involved in immune system testing will find the UCSF study useful. (Photo copyright: Elena Zhukova /University of California San Francisco.)
UCSF Study Details
UCSF researchers discovered that individuals who are COVID-19 “super dodgers” have “a mutation in the proteins that helps the immune system recognize what belongs to the body and what doesn’t,” Euronews reported.
The UCSF study showed that HLA-B*15.01—a Human Leukocyte Antigen (HLA) mutation—informs the body of the presence of SARS-CoV-2, regardless of whether it has encountered the invader before. The immune system then deploys T-cells [white blood cells called lymphocytes that help the immune system fight germs and protect the body from disease] to “eliminate” the coronavirus.
“Individuals with this B*15:01 mutation who have these cross-reactive T-cells seem to be particularly effective, very early in infection, at nuking—for lack of a better word—the virus before these folks experience any symptoms at all,” Jill Hollenbach, PhD, and immunogeneticist and Professor in the Department of Neurology and Department of Epidemiology and Biostatistics at UCSF, told STAT. Hollenbach led the team that discovered the gene mutation responsible for COVID-19 super dodgers.
“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,” according to a UCSF news release, which added, “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 far more likely—more than eight times—to avoid feeling sick.”
To find study participants, the team consulted The National Marrow Donor Program (NMDP) Be the Match Registry, which pairs donors with people needing transplants. It’s the largest registry of HLA volunteer donors in the United States. “Researchers suspected early on that HLA was involved, and fortunately a national registry existed that contained the data they were looking for,” the UCSF news release states.
To fully understand how COVID-19 affected the NMDP donors, the team utilized UCSF’s COVID-19 Citizen Science Study, a longitudinal cohort study on UCSF’s Eureka Digital Research Platform which uses a smartphone app developed by UCSF to learn how to predict SARS-CoV-2’s spread throughout the world and combat it.
About 30,000 people from the registry were followed through that first year of the COVID-19 pandemic, which featured frequent testing and no vaccine access for most, UCSF stated.
“We did not 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 internal medicine physician Mark Pletcher, MD, Professor of Epidemiology and Biostatistics at UCSF, in the news release. Pletcher’s practice focuses on prevention of cardiovascular disease.
The UCSF scientists dove deep to understand how HLA-B*15:01 tackled coronavirus, and together 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,” UCSF reported.
“It’s just one of these natural lucky breaks,” Hollenbach told STAT.
UCSF Findings Bring Hope for Improved Vaccines and Drug Therapies
HLA was a good hunch to follow. The UCSF researchers’ Nature paper claimed HLA to be “the most polymorphic and medically important human genomic region.” It noted that variations of HLA were linked to myriad diseases, especially viral infections.
“The strongest associations were seen with viral infections, and HLA was associated with rapid progression and viral load of human immunodeficiency virus (HIV), hepatitis B, and C … Also HLA class I and II alleles have been associated with severe acute respiratory syndrome caused by SARS-CoV,” the Nature paper noted.
“Specific focus on asymptomatic infection has the potential to further our understanding of disease pathogenesis and supports ongoing efforts towards vaccine development and the identification of potential therapeutic targets,” the UCSF researchers wrote in Nature.
Should further research and studies confirm these findings, it’s reasonable to speculate that, in a future outbreak of new strains of SARS-CoV-2, clinical laboratories could test individuals to identify those with the mutation making them unlikely to experience a serious infection.
Those individuals could work on the front lines of medical care with a lower risk of infection and serious disease. It might also mean that they would not need vaccinations at all.
—Kristin Althea O’Connor