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UCSF Researchers Identify Genetic Mutation That Promotes an Asymptomatic Response in Humans to COVID-19 Infection

Understanding why some people display no symptoms during a COVID-19 infection could lead to new precision medicine genetic tests medical labs could use to identify people with the mutated gene

New research from the University of California San Francisco (UCSF) may explain why some people could get COVID-19 but never test positive on a clinical laboratory test or develop symptoms despite exposure to the SARS-CoV-2 coronavirus.

According to the UCSF study, 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.

These scientific insights did not receive widespread news coverage but will be of interest to clinical laboratory managers and pathologists who oversee SARS-CoV-2 testing in their labs.

Jill Hollenbach, PhD

“Some people just don’t have symptoms at all,” Jill Hollenbach, PhD (above), Professor of Neurology at UCSF’s Weill Institute for Neurosciences and lead researcher in the study, told NBC News. “There’s something happening at a really fundamental level in the immune response that is helping those people to just completely wipe out this infection.” Identifying a genetic reason why some people are asymptomatic could lead to new precision medicine clinical laboratory diagnostics for COVID-19. (Photo copyright: Elena Zhukova /University of California San Francisco.)

Fortunate Gene Mutation

According to the Centers for Disease Control and Prevention’s (CDC) COVID Data Tracker, as of April 5, 2023, a total of 104,242,889 COVID-19 cases have been reported in the United States. However, according to a CDC Morbidity and Mortality Weekly Report (MMWR), “Traditional methods of disease surveillance do not capture all COVID-19 cases because some are asymptomatic, not diagnosed, or not reported; therefore, [knowing the true] proportion of the population with SARS-CoV-2 antibodies (i.e., seroprevalence) can improve understanding of population-level incidence of COVID-19.”

Jill Hollenbach, PhD, lead researcher in the UCSF study and Professor of Neurology at UCSF’s Weill Institute for Neurosciences, runs the Hollenbach Lab at UCSF. The lab specializes in the study of two important elements in human immune response:

She also participates in the COVID-19 HLA and Immunogenetics Consortium, a group of academic researchers, clinical laboratory directors, journal editors, and others who examine the role of HLA variations in determining COVID-19 risk.

Hollenbach’s research identified an HLA variant—known as HLA-B*15:01—that causes the human immune system to react quickly to SARS-CoV-2 and “basically nuke the infection before you even start to have symptoms,” she told NPR.

“It’s definitely luck,” she added. “But, you know, this [gene] mutation is quite common. We estimate that maybe one in 10 people have it. And in people who are asymptomatic, that rises to one in five.”

The researchers published their findings on the medRxiv preprint server titled, “A Common Allele of HLA Mediates Asymptomatic SARS-CoV-2 Infection.” The UCSF study has not yet been peer-reviewed.

UCSF Study Methodology

“HLA variants are among the strongest reported associations with viral infections,” the UCSF study notes. So, the researchers theorized that HLA variations play a role in asymptomatic SARS-CoV-2 infections as well.

To conduct their study, shortly after the SARS-CoV-2 outbreak in 2020, the researchers recruited approximately 30,000 volunteer bone marrow donors from the National Marrow Donor Program to respond to periodic questions via a smartphone app or website. Because HLA variations can determine appropriate matches between donors and recipients, the database includes information about their HLA types.

Each week, respondents were asked to report if they had been tested for SARS-CoV-2. Each day, they were asked to report whether they had symptoms associated with COVID-19. “We were pretty stringent in our definition of asymptomatic,” Hollenbach told NBC News. “[The respondents couldn’t] even have a scratchy throat.”

The researchers eventually identified a cohort of 1,428 people who had tested positive for SARS-CoV-2 between February 2020 and April 30, 2021, before vaccines were widely available. Among these individuals, 136 reported no symptoms for two weeks before or two weeks after a positive test.

“Overall, one in five individuals (20%) who remained asymptomatic after infection carried HLA-B*15:01, compared to 9% among patients reporting symptoms,” the researchers wrote in their medRxiv preprint. Study participants with two copies of the gene were more than eight times more likely to be asymptomatic.

The UCSF researchers also looked at four other HLA variants and found none to be “significantly associated” with lack of symptoms. They confirmed their findings by reproducing the HLA-B association in two additional independent cohorts, one from an earlier study in the UK and the other consisting of San Francisco-area residents.

Individuals in the latter group had either tested positive for SARS-CoV-2 or reported COVID symptoms, and their DNA was analyzed to determine their HLA types.

Pre-existing T-Cell Immunity May Reduce Severity of COVID-19 Infection

The UCSF researchers also attempted to determine how HLA-B*15:01 plays a role in knocking out SARS-CoV-2 infections. They noted previous research that indicated previous exposure to seasonal coronaviruses, such as common cold viruses, could limit the severity of COVID-19. The scientists hypothesized that pre-existing T-cell immunity in HLA-B carriers may be the key.

The COVID-19 HLA and Immunogenetics Consortium website describes how HLA and T-cells work together to ward off disease. HLA “proteins are found on the surface of all cells except red-blood cells.” They’re “like windows into the inner workings of a cell,” and T-cells use the molecules to determine the presence of foreign proteins that are likely signs of infection. “Activated T-cells can kill infected cells, or activate B-cells, which produce antibodies in response to an infection,” the website explains.  

Hollenbach’s research team analyzed T-cells from pre-pandemic individuals and observed that in more than half of HLA-B carriers, the T-cells were reactive to a SARS-CoV-2 peptide. The scientists corroborated the hypothesis by examining crystal structures of the HLA-B*15:01 molecule in the presence of coronavirus spike peptides from SARS-CoV-2 and two other human coronaviruses: OC43-CoV and HKU1-CoV.

“Altogether, our results strongly support the hypothesis that HLA-B*15:01 mediates asymptomatic COVID-19 disease via pre-existing T-cell immunity due to previous exposure to HKU1-CoV and OC43-CoV,” the researchers wrote.

Can Genes Prevent COVID-19 Infections?

Meanwhile, researchers at The Rockefeller University in New York City are attempting to go further and see if there are mutations that prevent people from getting infected in the first place. NPR reported that they were seeking participants for a study seeking to identify so-called “superdodger” genes.

“You fill out a questionnaire online about your exposures to SARS-CoV-2,” explained Jean-Laurent Casanova, MD, PhD, professor, senior attending physician, and head of the St. Giles Laboratory of Human Genetics of Infectious Diseases at The Rockefeller University, who is leading the study.

Study participants identified as possibly having superdodger genes receive a kit designed to collect saliva samples, after which the researchers sequence the respondents’ genomes. “We hope that in a group of 2,000 to 4,000 people, some people will have genetic mutations that tell us why they’re resistant to infection,” Casanova told NPR.

All this genetic research is in very early stages. But results are promising and may lead to new precision medicine clinical laboratory tests for identifying people who are predisposed to having an asymptomatic response to COVID-19 infection. That in turn could help scientists learn how to moderate or even eliminate symptoms in those unfortunate people who suffer the typical symptoms of the disease.   

—Stephen Beale

Related Information:

A Common Allele of HLA Mediates Asymptomatic SARS-CoV-2 Infection

What People with ‘Super Immunity’ Can Teach Us about COVID and Other Viruses

So, You Haven’t Caught COVID Yet. Does That Mean You’re a Superdodger?

If You Haven’t Gotten COVID Yet, This Might Be Why

Trends in Number of COVID-19 Cases and Deaths in the US Reported to CDC, by State/Territory

UC San Francisco Researchers Discover Why Some People Are Asymptomatic When Infected with COVID-19

Seroprevalence of Infection-Induced SARS-CoV-2 Antibodies—United States, September 2021–February 2022

CDC National Wastewater Surveillance System Locates and Tracks SARS-CoV-2 Coronavirus in the Public’s Wastewater

Smaller cities and rural towns are finding the NWSS a useful early warning tool for tracking COVID-19 in their communities

In a move that mirrors similar programs around the world, the federal Centers for Disease Control and Prevention (CDC) now monitors sewage nationwide and records levels of SARS-CoV-2 in an effort to prevent new outbreaks of COVID-19 and spot any new variants of the coronavirus.

Advances in gene sequencing technologies are enabling the CDC’s National Wastewater Surveillance System (NWSS), and in many communities, clinical laboratories and health system laboratories have worked with local health authorities to test wastewater since onset of the pandemic.

Dark Daily first covered the CDC’s intention to develop the NWSS in a 2020 ebriefing, titled, “CDC, HHS Create National Wastewater Surveillance System to Help Monitor and Track Spread of COVID-19.” The CDC detailed its latest progress implementing the NWSS in a recent media telebriefing.

“What started as a grassroots effort by academic researchers and wastewater utilities has quickly become a nationwide surveillance system with more than 34,000 samples collected representing approximately 53 million Americans,” noted epidemiologist Amy Kirby, PhD (above) during the telebriefing.

Kirby is a Senior Service Fellow in the Waterborne Disease Prevention Branch at the CDC.

“Currently, CDC is supporting 37 states, four cities, and two territories to help develop wastewater surveillance systems in their communities. More than 400 testing sites around the country have already begun their wastewater surveillance efforts,” she added.

Amy Kirby, PhD
“Estimates suggests between 40% and 80% of people with COVID-19 shed viral RNA in their feces, making wastewater and sewage an important opportunity for monitoring the spread of infection,” said epidemiologist Amy Kirby, PhD (above), a Senior Service Fellow in the Waterborne Disease Prevention Branch at the CDC. The NWSS’ findings could enable public health officials to better allocate mobile clinical laboratory testing and COVID-19 vaccination sites around the country. This would be especially beneficial in rural and underserved healthcare populations. (Photo copyright: Center for Global Safe Water, Sanitation, and Hygiene.)

Genetic Sequencing Enables Tracking of Virus and Bacteria

At the time of the telebriefing, the federal agency anticipated having an additional 250 sites online within a few weeks and even more sites added within the coming months. Many of the participating sites are sequencing the genes of their biological samples and reporting that data to the CDC.

“So, we’ve seen from very early days in the pandemic that rates of detection in wastewater correlate very well with other clinical indicators, like pace rates and hospitalization and test positivity,” Kirby stated. “That data continues to come in and it continues to be a very solid indicator of what’s going on in the community.”

Wastewater, also referred to as sewage, includes water from toilets, showers, and sinks that may contain human fecal matter and water from rain and industrial sources. To use the CDC’s wastewater surveillance system:

  • Wastewater is collected from a community area served by the surveillance system as it flows into a local water treatment plant.
  • Collected samples are sent to an environmental or public health laboratory where they are tested for SARS-CoV-2.
  • Health departments submit the testing data to the CDC through the online NWSS Data Collection and Integration for Public Health Event Response (DCIPHER) portal.
  • The DCIPHER system then analyzes the data and reports the results back to the health department for use in their COVID-19 response.

Beginning in February 2022, members of the public can view the results of collected data online through the CDC’s COVID Data Tracker.

Wastewater Sampling Is a ‘Critical Early Warning System’

According to the CDC NWSS website, there are many advantages to using wastewater surveillance in the fight against COVID-19, including:

  • Wastewater can capture the presence of the virus shed by people both with and without symptoms.
  • Health officials can determine if infections are increasing or decreasing within a certain monitoring site.
  • Wastewater surveillance does not depend on people having access to healthcare or the availability of COVID-19 testing.
  • It is possible to implement wastewater surveillance in many communities as nearly 80% of the US population are served by municipal wastewater collection systems.

“These built-in advantages can inform important public health decisions, such as where to allocate mobile testing and vaccination sites,” Kirby said. “Public health agencies have also used wastewater data to forecast changes in hospital utilization, providing additional time to mobilize resources and preparation for increasing cases.”

The wastewater sampling represents a critical early warning system for COVID-19 surges and variants, and the CDC hopes this type of sampling and research can be utilized in the future for other infectious diseases. 

“Wastewater surveillance can be applicable to a wide variety of health concerns. And so, we are working to expand the National Wastewater Surveillance platform to use it for gathering data on other pathogens, and we expect that work to commence by the end of this year,” Kirby said. “Our targets include antibiotic resistance, foodborne infections like E. Coli, salmonella, norovirus, influenza, and the emerging fungal pathogen Candida Auris.”

Critical Surveillance Tool for Microbiology Laboratories

Independent of the nation’s network of public health laboratories, expansion of this program may give microbiology and clinical laboratories in smaller cities and rural towns an opportunity to test wastewater specimens in support of local wastewater monitoring programs.

As the CDC develops this surveillance network into a more formal program, microbiology labs may find it useful to learn which infectious diseases are showing up in their localities, often days or weeks before any patients test positive for the same infectious agents.

That would give pathologists and clinical laboratory leaders an early warning to be on the alert for positive test results of infectious diseases that wastewater monitoring has confirmed exist in the community.   

JP Schlingman

Related Information:

Studies Finding Remnants of SARS-CoV-2 in Sewage Suggest COVID-19 May Not Have Originated at Wuhan Market, Some Scientists Dispute the Findings

CDC Turns to Poop Surveillance for Future COVID Monitoring

National Wastewater Surveillance System (NWSS)

Transcript for CDC Media Telebriefing: COVID-19 Wastewater Surveillance

CDC, HHS Create National Wastewater Surveillance System to Help Monitor and Track Spread of COVID-19