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Population Differences in SARS-CoV-2 Response Uncovered in Single-Cell Sequencing Study


NEW YORK – An international team led by investigators in France has teased out individual and population differences in responses to SARS-CoV-2 or influenza infections using single-cell gene expression analyses — work published in Nature on Wednesday.

"Overall, our results highlight the value of single-cell approaches in capturing the full diversity of peripheral immune responses to RNA viruses, particularly SARS-CoV-2, and provide insights into environmental, genetic, and evolutionary drivers of immune response variation across individuals and populations," co-senior and co-corresponding authors Lluis Quintana-Murci, a researcher at the Pasteur Institute and the College of France, and Maxime Rotival, an investigator at the Pasteur Institute, and their colleagues wrote.

Using single-cell RNA sequencing, the researchers profiled more than 1 million individual peripheral blood mononuclear cells from 222 healthy donors with Central African, European, and East Asian ancestry who had not been infected with SARS-CoV-2, including a subset of cells that were exposed to SARS-CoV-2, influenza A virus, or a mock control for six hours.

The team's analyses highlighted nearly 22 expression clusters representing cells in myeloid, B cell, CD4-positive T cell, CD8-positive T cell, and natural killer cell lineages, while unearthing specific responses related to the type of virus involved, individuals' ancestry, and the proportions of different cell types in the blood.

Along with a distinct pro-inflammatory signature found in myeloid immune cells responding to SARS-CoV-2, for example, the single-cell expression profiles pointed to "weaker, but more heterogeneous, interferon-stimulated gene activity" after exposure to SARS-CoV-2 relative to influenza A, the authors explained.

The single-cell transcriptomics data also made it possible to pick up ancestry-related differences in the proportion of different immune cell types within each of the immune lineages considered, even in the non-simulated control cells.

At least some of these cellular composition differences appeared to reflect differences in latent cytomegalovirus rates between populations, pointing to the importance of environmental contributors in shaping the immune system.

At the basal state, the team flagged almost 3,400 differentially expressed genes across populations, while 898 genes showed differential responses to SARS-CoV-2 and more than 650 genes had population-related responses to influenza A virus exposure.

The researchers also looked at immune differences between populations stemming from processes such as natural selection, including differences potentially related to levels of Neanderthal admixture and ancestry, and described higher-than-usual levels of variants related to SARS-CoV-2 response in individuals of East Asian ancestry.

When they incorporated expression quantitative trait locus clues for the ancestry groups, cell types, and viral exposures considered in the study, meanwhile, the investigators tracked down more than 1,500 viral stimulus response-related QTLs influencing the expression of 1,213 genes.

The variant with the strongest ties to SARS-CoV-2 response fell in the myeloid cell gene MMP1, they reported, noting that this gene has been linked to COVID-19 severity in a past study.

The team also saw broader links between the gene expression shifts identified in SARS-CoV-2-exposed cells and COVID-19 susceptibility or severity loci or genes identified with a transcriptome-wide association analysis or in prior genome-wide association studies.

"[QTL colocalization] and transcriptome-wide association analyses reveal an overlap between the genetic basis of immune responses to SARS-CoV-2 and COVID-19 severity," the authors wrote, "providing insights into the factors contributing to current disparities in COVID-19 risk."