News, Analysis, Trends, Management Innovations for
Clinical Laboratories and Pathology Groups
Hosted by Robert Michel

News, Analysis, Trends, Management Innovations for
Clinical Laboratories and Pathology Groups
Hosted by Robert Michel
Sign In

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

Apr 12, 2023 | Laboratory News, Laboratory Testing, Molecular Diagnostics, Genetic Testing, Whole Gene Sequencing, Precision Medicine

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

‘Barcoding’ Cells in Nematodes Could Bring Advances and New Medical Laboratory Tools for Treatment of Cancer and Other Chronic Diseases

Nov 17, 2017 | Laboratory Instruments & Laboratory Equipment, Laboratory Management and Operations, Laboratory News, Laboratory Operations, Laboratory Pathology, Laboratory Testing, Management & Operations

Ongoing research at the University of Washington promises new methods for identifying and cataloging large numbers of cells quickly, which could lead to more individualized treatments in support of precision medicine initiatives

Researchers have found a new method for identifying specific cell types by groups, a breakthrough that some experts say could lead to new and more accurate methods for diagnosing and treating disease in individual patients, and new tools for fighting cancer and other chronic diseases. If this happens, both clinical laboratories and anatomic pathology labs would benefit from this technology.

A study published in the journal Science titled, “Comprehensive Single-Cell Transcriptional Profiling of a Multicellular Organism,” describes advances in cataloging cells that are much faster than the traditional method of using a microscope. The research is still in the experimental stage, but it is being hailed as both exciting and promising by experts in the field.

Barcoding Large Numbers of Cells for Viewing Simultaneously

To test their method, researchers from the University of Washington (UW) sequenced each cell of an individual Caenorhabditis elegans (nematode). Nematodes are transparent roundworms that have been extensively studied making them ideal for the UW study, since much information exists about their cellular structure.

The researchers developed a strategy they dubbed “single-cell combinatorial indexing RNA sequencing,” or “sci-RNA-seq” for short, to profile the transcriptomes of nuclei. A New York Times article on the study describes sci-RNA-seq as a kind of barcoding that shows which genes are active in each cell.

“We came up with this scheme that allows us to look at very large numbers of cells at the same time, without ever isolating a single cell,” noted Jay Shendure, PhD, MD, Professor of Genome Sciences at the University of Washington.

The UW researchers used sci-RNA-seq to measure the activity in 42,035 cells at the same time. Once all of the cells were tagged, or barcoded, the researchers broke them open so the sequences of tags could be read simultaneously.

“We defined consensus expression profiles for 27 cell types and recovered rare neuronal cell types corresponding to as few as one or two cells,” wrote the researchers in their published study.

Because such a rich body of research on nematodes exists, the researchers could easily compare the results that got to those procured in previous studies.

Jay Shendure, MD, PhD (above), Professor of Genomic Sciences at the University of Washington, and an Investigator at the Howard Hughes Medical Institute, was just a graduate student when his work with genetics led to the development of today’s next-generation gene sequencing technologies. His new cell-type identification technology could eventually be used by clinical laboratories and anatomic pathology groups to diagnose disease. (Photo copyright: Howard Hughes Medical Institute.)

One Giant Leap for Medical Diagnostics

Identifying cell types has been a challenge to the medical community for at least 150 years. It is important for scientists to understand the most basic unity of life, but it has only been in the last few years that researchers have been able to measure transcriptomes in single cells. Even though the research so far is preliminary, the scientific community is excited about the results because—should the methods be refined—it could mean a great leap forward in the field of cell-typing.

However, the study did not identify all of the cell types known to exist in a nematode. “We don’t consider this a finished project,” stated Shendure in a New York Times article.

Nevertheless, researchers not associated with the study feel confident about the promise of the work. Cori Bargmann, PhD, a neurobiologist and Torsten N. Wiesel Professor at The Rockefeller University, and an Investigator for the Howard Hughes Medical Institute from 1995 to 2016, states that the results “will be valuable for me and for the whole field,” adding, “Of course, there’s more to do, but I am pretty optimistic that this can be solved.”

“The ability to measure the transcriptomes of single cells has only been feasible for a few years, and is becoming an extremely popular assay,” wrote Valentine Svensson, predoctoral fellow et al, of EMBL-EBI in the UK, in a paper titled, “Exponential Scaling of Single-Cell RNA-Seq in the Last Decade.” He added, “Technological developments and protocol improvements have fueled a consistent exponential increase in the numbers of cells studied in single cell RNA-seq analyses.” The UW research represents another such improvement.

Human Cell Atlas—Understanding the Basis of Life Itself

There are approximately 37-trillion cells in the human body and scientists have long believed there are 200 different cell types. Thus, there is an enormous difference between a nematode and a human body. For medical science to benefit from these studies, massive numbers of human cells must be identified and understood. Efforts are now underway to catalog and map them all.

The Human Cell Atlas (HCA) is an effort to catalog all of those disparate cell types. The mission of HCA is “To create comprehensive reference maps of all human cells—the fundamental units of life—as a basis for both understanding human health and diagnosing, monitoring, and treating disease.”

According to HCA’s website, having the atlas completed will impact our understanding of every aspect of human biology, from immunologic diseases to cancer. Aviv Regev, PhD, of the Broad Institute at MIT, who also is an Investigator with the HHMI and is co-chair of the organizing committee at the Human Cell Atlas notes, “The human cell atlas initiative will work through organs, tissues, and systems.”

One of the many complications of creating the atlas is that the locations of cells vary in humans. “The trick,” Regev noted in the New York Times article, “is to relate cells to the place they came from.” This would seem to be at the heart of the UW researchers’ new method for “barcoding” groups of cells.

Just as sequencing the entire human genome has brought about previously unimagined advances in science, so too will the research being conducted at the University of Washington, as well as the completion of the Human Cell Atlas Project. It is possible that pursuing the goal of quickly identifying and cataloging cells will lead to advances in anatomic pathology, and allow medical laboratory scientists to better interpret genetic variants, ultimately bringing healthcare closer to the delivery of true precision medicine.

—Dava Stewart

Related Information:

Comprehensive Single-Cell Transcriptional Profiling of a Multicellular Organism

A Speedier Way to Catalog Human Cells (All 37 Trillion of Them)

Exponential Scaling of Single-Cell RNA-Seq In the Last Decade

Human Cell Atlas

Genetic Fingerprint Helps Researchers Identify Aggressive Prostate Cancer from Non-Aggressive Types and Determine if Treatment Will Be Effective

Big Data Projects at Geisinger Health Are Beginning to Help Physicians Speed Up Diagnosis and Improve Patient Care

Biomarker Trends Are Auspicious for Pathologists and Clinical Laboratories

Pathologists and Clinical Laboratories May Soon Have a Test for Identifying Cardiac Patients at Risk from Specific Heart Drugs by Studying the Patients’ Own Heart Cells

New York Genome Center Opens New Gene Sequencing and Bioinformatics Facility in Downtown Manhattan

Nov 11, 2013 | Digital Pathology, Instruments & Equipment, Laboratory Management and Operations, Laboratory News, Laboratory Pathology

The Center brings together scientists from around the city to translate promising research into medical innovations to treat, prevent and manage disease

Gene sequencing is going big time in the Big Apple. Last month the New York Genome Center (NYGC) moved into a state-of-the-art, 170,000-square-foot genome sequencing and biometrics research building. New York City is putting down its marker to claim a leading role in advancing genetic knowledge.

What makes this development notable for the clinical laboratory industry and the anatomic pathology profession is the fact that cities across the nation are investing substantial amounts of capital to create their own genetic and biotech research and development hubs. Their common objective is to bring together all the expertise, financial support, and business acumen needed to create a job-creating critical mass in the fields of biotech and genetic medicine. (more…)

;