Researchers from the University of Sheffield and Stanford University say they have discovered that there are specific genetic signals in people who develop severe coronavirus infection.

It is known that age, body mass index, and pre-existing health problems account for some of the disparities, but genetics also plays a significant role. The current study “Multiomic analysis reveals cell-type-specific molecular determinants of COVID-19 severity,” published in Cell Systems, aimed to address why some people with COVID-19 become seriously ill or die, while others have few, if any, symptoms.

The scientists used a machine learning tool named RefMap, which can find patterns in vast amounts of data, to help identify the genetic basis for complex and poorly understood diseases. The identified more than 1,000 genes linked to the development of severe COVID-19 cases that required breathing support, or were fatal. They were also able to identify specific types of cells in which those genes act up.

The study is one of the first to link coronavirus-associated genes to specific biological functions.

Corona Virus covid-19 illustration
Researchers used several large data sets to unpack the genetics behind severe COVID-19. [ Images]
“The determinants of severe COVID-19 in healthy adults are poorly understood, which limits the opportunity for early intervention. We present a multiomic analysis using machine learning to characterize the genomic basis of COVID-19 severity. We use single-cell multiome profiling of human lungs to link genetic signals to cell-type-specific functions,” write the investigators.

“We discover >1,000 risk genes across 19 cell types, which account for 77% of the SNP-based heritability for severe disease. Genetic risk is particularly focused within natural killer (NK) cells and T cells, placing the dysfunction of these cells upstream of severe disease. Mendelian randomization and single-cell profiling of human NK cells support the role of NK cells and further localize genetic risk to CD56bright NK cells, which are key cytokine producers during the innate immune response. Rare variant analysis confirms the enrichment of severe-disease-associated genetic variation within NK-cell risk genes.

“Our study provides insights into the pathogenesis of severe COVID-19 with potential therapeutic targets.”

“During the research we discovered the genetic architecture underlying coronavirus infection, and found that these 1,000 genes account for three quarters of the genetic drivers for severe COVID-19,” said Johnathan Cooper-Knock, PhD, National Institute for Health and Care Research (NIHR) clinical lecturer in the department of neuroscience at the University of Sheffield and co-author of the study. “This is significant in understanding why some people have had more severe symptoms of COVID-19 than others.”

Michael P. Snyder, PhD, principal investigator in the department of genetics at Stanford, led the study in collaboration Stanford genetics instructor Sai Zhang, PhD, and Cooper-Knock, who is currently a Stanford visiting scholar.

The research process

The research team used several large data sets to unpack the genetics behind severe COVID-19. The first data set contained genetic information from healthy human lung tissue. The data helped identify gene expression in 19 different types of lung cells, including epithelial cells that line the respiratory tract and are the first defense against infection.

Other data came from the COVID-19 Host Genetics Initiative, one of the largest genetic studies of critically ill coronavirus patients. The researchers looked for genetic clues in the data–single nucleotide polymorphisms–that might indicate if someone is at a higher risk for severe COVID-19. They tracked whether some mutations occurred more or less often in COVID-19 patients with severe disease.

Mutations that continued to appear, or were notably absent, in the patients who developed severe COVID-19 suggested those variations might be behind the infection’s severity.

But genetic mutations on their own can be difficult to interpret. To better understand their findings the team used other data describing which regions of the genome are important for different cell types within lung tissue. By overlapping the mutations onto the cell-specific genomes the researchers could pinpoint which genes were dysfunctioning and within which cell-types.

Risk genes

The researchers also wanted to know which types of cells harbored faulty gene expression. Through their machine learning tool, they determined that severe COVID-19 is largely associated with a weakened response from two well-known immune cells, i.e., natural killer (NK) cells and T cells. NK cells and a subtype called CD56 bright are considered the most important.

“NK cells, which humans are born with and are the body’s first line of defense against infection, are known for their ability to destroy viruses and cancer cells,” noted Cooper-Knock. “NK cells also help produce a range of immune system proteins called cytokines. One cytokine, interferon gamma, is a key activator of immune cells. Acting in concert with interferon gamma, NK cells mount an immediate and coordinated defense against viral infections.

“NK cells are like the generals directing the war. They mobilize other immune cells, telling them where to go and what to do. We found that in people with severe coronavirus infection, critical genes in NK cells are expressed less, so there’s a less robust immune response. The cell isn’t doing what it’s supposed to do.”

Stanford’s Snyder likened COVID-19 risk genes to harmful variants of the BRCA genes that predispose some people to breast and ovarian cancer.

“Our findings lay the foundation for a genetic test that can predict who is born with an increased risk for severe COVID-19,” he said. “Imagine there are 1,000 changes in DNA linked to severe COVID-19. If you have 585 of these changes, that might make you pretty susceptible, and you’d want to take all the necessary precautions.”

Cooper-Knock pointed out that drugs that kickstart sluggish NK cells are already proposed to treat some types of cancer. “The drugs bind to receptors on the NK cells and trigger them to have a more robust response,” he explained, noting that trials of NK cell infusions for severe COVID-19 are underway.”

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