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Genetic Ancestry Shapes Immune Response to Influenza – Genetic Engineering & Biotechnology News

Pathogenic viruses exert the strongest selection pressure in human evolution, particularly with the increased potential for long-distance transmission. A new study tests whether population-level differences in genetic polymorphisms mediate differences in immune response to viral infection. The study is valuable not just for insights into human evolution but for explaining racial and ethnic differences in susceptibility to viral epidemics in the present day.
Combining single-cell RNA sequencing (scRNA-seq) with in vitro influenza A virus (IAV)-infection assays in peripheral blood mononuclear cells (PBMCs), the new study led by scientists at the University of Chicago has found that men of European and African genetic ancestry activate different immune pathway components in response to influenza infection. The study also showed genetic ancestry–linked genes are enriched among genes that determine COVID-19 disease severity. This the authors said, indicates early immune response contributes to ancestry-associated differences in the outcomes of many viral infections.
“Our findings suggest immune response variation may interact with or exacerbate environment-driven health disparities in viral susceptibility and morbidity, which occur for both influenza and COVID-19,” said Luis Barreiro, PhD, associate professor in the department of medicine at the University of Chicago and senior author of the paper.
The study was published in Science, in an article titled, “Genetic ancestry effects on the response to viral infection are pervasive but cell type specific.”
Haley Randolph, a graduate student at the University of Chicago and first author of the study said, “The lab has been interested in understanding how individuals from diverse populations respond differently to infectious diseases. In this study, we wanted to look at the differences in how various cell types respond to viral infection.”
PBMCs are a diverse set of specialized immune cells that play important roles in the body’s response to infection. The researchers exposed PBMCs from men of different degrees of European and African ancestry to the flu virus in a laboratory setting and examined gene expression patterns in the cells. This allowed them to examine gene signatures of a variety of immune cell types to determine how flu infection affects each cell type.
“We used scRNA-seq to study how specific immune cell types within the mixed pool of immune cells respond to the virus. In contrast to bulk (traditional) RNA-seq, scRNA-seq allows us to evaluate how individual cells are transcriptionally altered in response to the virus without having to sort the cells, therefore preserving the critical interactions observed in vivo between the many different cell types involved in an efficient immune response to influenza A,” said Barreiro.
The authors found thousands of genes for which gene expression levels in response to influenza A infection varied significantly between individuals of European and African ancestry, demonstrating ancestry effects are pervasive. “The most striking ancestry-linked differences were observed for the type I interferon response. We found that individuals with a higher proportion of European ancestry showed an increase in type I interferon pathway activity during early influenza infection,” said Barreiro. “This correlated with a greater capacity to limit viral replication at a later time point, suggesting that the differences observed may have a direct impact on the body’s ability to control the virus.”
Interferons play a critical role in fighting viral infections. Type I interferon response has been associated with differences in the severity of COVID-19 disease. Barreiro added, “Unexpectedly, this central pathway to our defense against viruses appears to be amongst the most divergent between individuals from African and European ancestry.”
The researchers noted differences in gene expression across different PBMC cell types. This shows that differences in overall immune response among the genetically diverse cohorts are not based on changes in a single type of immune cell. “Genetic ancestry effects are common but highly cell type specific,” the authors noted.
Epidemiological studies have shown, non-Hispanic Black Americans are more likely to be hospitalized due to severe flu symptoms compared to other racial ethnicities. Differences in immune pathway activation may contribute to this disparate outcome, the current study suggests. The researchers point out that their results do not indicate genetic differences in disease susceptibility. Environmental and lifestyle factors may differ between the groups, influencing gene expression and in turn, immune response.
“There’s a strong relationship between the interferon response and the proportion of the genome that is of African ancestry, which might make you think it’s genetic, but it’s not that simple,” said Barreiro. “Genetic ancestry also correlates with environmental differences. A lot of what we’re capturing could be the result of other disparities in our society, such as systemic racism and healthcare inequities. Although some of the differences we show in the paper can be linked to specific genetic variation, showing that genetics do play some role, such genetic differences are not enough to fully explain the differences in the interferon response.”
When the researchers compared the genes associated with differences in the severity of COVID-19 and flu, many of the same genes showed significant differences in expression between individuals of European and African ancestry. “We didn’t study COVID-19 patient samples as part of this study,” said Barreiro. “But the overlap between these gene sets suggests that there may be some underlying biological differences, influenced by genetic ancestry and environmental effects, that might explain the disparities we see in COVID-19 outcomes.”
The authors noted, “Given the central role played by interferons in conferring antiviral activity to host cells, our findings have potential clinical implications not only for influenza infection but also for other viruses, including SARS-CoV-2, for which the timing and magnitude of interferon-mediated antiviral responses are associated with disease progression and severity.”
In future experiments, the team intends to identify factors that affect differences in interferon and overall immune responses. This will allow physicians to predict the risk of symptom severity in individuals infected by different viruses. “We are currently expanding this line of research to study ancestry differences in immune responses among COVID-19 patients. We are also expanding our study to a broader array of ancestry groups,” Barreiro added.
The study was funded by the National Institutes of Health and the National Science Foundation.
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