The Genetic Edge: Unmasking the Secret of COVID-19 “Super Dodgers”

Scientists have discovered a gene variant, HLA-B*15:01, linked to asymptomatic COVID-19First identified in 2019 in Wuhan, China, COVID-19, or Coronavirus disease 2019, (which was originally called "2019 novel coronavirus" or 2019-nCoV) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It has spread globally, resulting in the 2019–22 coronavirus pandemic.” data-gt-translate-attributes=”[{“attribute”:”data-cmtooltip”, “format”:”html”}]”>COVID-19 cases, opening potential avenues for new treatments and vaccines.

People who contract COVID-19 but never develop symptoms – the so-called super dodgers – may have a genetic ace up their sleeve. They’re more than twice as likely as those who become symptomatic to carry a specific gene variation that helps them obliterate the virusA virus is a tiny infectious agent that is not considered a living organism. It consists of genetic material, either DNA or RNA, that is surrounded by a protein coat called a capsid. Some viruses also have an outer envelope made up of lipids that surrounds the capsid. Viruses can infect a wide range of organisms, including humans, animals, plants, and even bacteria. They rely on host cells to replicate and multiply, hijacking the cell's machinery to make copies of themselves. This process can cause damage to the host cell and lead to various diseases, ranging from mild to severe. Common viral infections include the flu, colds, HIV, and COVID-19. Vaccines and antiviral medications can help prevent and treat viral infections.” data-gt-translate-attributes=”[{“attribute”:”data-cmtooltip”, “format”:”html”}]”>virus, according to a new study led by UC San Francisco researchers.

The paper, published recently in the journal Nature, offers the first evidence that there is a genetic basis for asymptomatic SARS-CoV-2Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the official name of the virus strain that causes coronavirus disease (COVID-19). Previous to this name being adopted, it was commonly referred to as the 2019 novel coronavirus (2019-nCoV), the Wuhan coronavirus, or the Wuhan virus.” data-gt-translate-attributes=”[{“attribute”:”data-cmtooltip”, “format”:”html”}]”>SARS-CoV-2. The research helps to solve the mystery of why some people can be infected without ever getting sick from COVID-19.

The Role of the HLA Genetic Variation

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 lightning 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.

The peptide NQK-Q8 (light color), a piece of SARS-CoV-2 spike protein that the virus uses to enter cells, bound to the HLA-B*15:01 groove (orange). The illustration is based on the crystal structure of HLA-B*15:01 in complex with spike derived peptide NQKLIANQF from SARS-CoV-2 virus (PDB Entry – 8ELH) published by Augusto et al., 2023 (Nature). Credit: André Luiz Lourenço

“If you have an army that’s able to 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 a member of the Weill Institute for Neurosciences at UCSF. “It’s like having soldiers that are prepared for battle and already know what to look for, and that these are the bad guys.”

Prevalence and Impact of the HLA-B*15:01 Mutation

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 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.

Data Gathering and Analysis

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 Program/Be The Match, the largest registry of HLA-typed volunteer donors in the U.S., matches donors with people who need 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 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, a professor of epidemiology and biostatistics at UCSF.

Sample Limitations and Findings

The primary study group was limited to those who self-identified as white because the final set of study respondents did not have enough people in it from other ethnic and racial groups to analyze.

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.

“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 avoid future pandemics,” said Martin Maiers, vice president of research at the National Marrow Donor Program/Be The Match.

Understanding the Immune Response

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 recognize 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.

Reference: “A common allele of HLA is associated with asymptomatic SARS-CoV-2 infection” by Danillo G. Augusto, Lawton D. Murdolo, Demetra S. M. Chatzileontiadou, Joseph J. Sabatino Jr, Tasneem Yusufali, Noah D. Peyser, Xochitl Butcher, Kerry Kizer, Karoline Guthrie, Victoria W. Murray, Vivian Pae, Sannidhi Sarvadhavabhatla, Fiona Beltran, Gurjot S. Gill, Kara L. Lynch, Cassandra Yun, Colin T. Maguire, Michael J. Peluso, Rebecca Hoh, Timothy J. Henrich, Steven G. Deeks, Michelle Davidson, Scott Lu, Sarah A. Goldberg, J. Daniel Kelly, Jeffrey N. Martin, Cynthia A. Vierra-Green, Stephen R. Spellman, David J. Langton, Michael J. Dewar-Oldis, Corey Smith, Peter J. Barnard, Sulggi Lee, Gregory M. Marcus, Jeffrey E. Olgin, Mark J. Pletcher, Martin Maiers, Stephanie Gras and Jill A. Hollenbach, 19 July 2023, Nature.
DOI: 10.1038/s41586-023-06331-x

Co-authors: Additional authors at UCSF include Mark J. Pletcher, MD, MPH; Jeffrey E. Olgin, MD; Gregory M. Marcus, MD, MAS; Sulggi Lee, MD, PhD; Jeffrey N. Martin, MD, PhD; J. Daniel Kelly, MD, PhD, MPH; Sarah A. Goldberg, MAS; Scott Lu, MD; Michelle Davidson, MD, MPH; Steven G. Deeks, MD; Timothy J. Henrich, MD; Michael J. Peluso, MD; Kara Lynch, PhD; Danillo G. Augusto, PhD; Joseph J. Sabatino, Jr., MD, PhD; Tasneem Yusufali, MS; Noah D. Peyser, PhD; Gurjot Gill; Fiona Beltran;  Cassandra Yun; Rebecca Hoh; Xochitl Butcher; Kerry Kizer; Karoline Guthrie; Victoria Murray; Vivian Pae; Sannidhi Sarvadhavabhatla.

Funding: The study was supported by the National Institutes of HealthThe National Institutes of Health (NIH) is the primary agency of the United States government responsible for biomedical and public health research. Founded in 1887, it is a part of the U.S. Department of Health and Human Services. The NIH conducts its own scientific research through its Intramural Research Program (IRP) and provides major biomedical research funding to non-NIH research facilities through its Extramural Research Program. With 27 different institutes and centers under its umbrella, the NIH covers a broad spectrum of health-related research, including specific diseases, population health, clinical research, and fundamental biological processes. Its mission is to seek fundamental knowledge about the nature and behavior of living systems and the application of that knowledge to enhance health, lengthen life, and reduce illness and disability.” data-gt-translate-attributes=”[{“attribute”:”data-cmtooltip”, “format”:”html”}]”>National Institutes of Health (R01AI159260), (3U2CEB021881-05S1) and (R21HG012386); and the National Health and Medical Research Council and the, Medical Research Future Fund in Australia.