Study analyzes response of individuals from diverse populations to infections

A recent study from the University of Chicago has identified differences in immune pathway activation to influenza infection between people of European and African genetic ancestry. The majority of the genes that were linked to these differences in the immune response to the flu are also enhanced among genes that associate with COVID-19 disease severity. The research was published on November 26^th, 2021 in the Science journal.

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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.”

Haley Randolph, Study First Author and Graduate Student, University of Chicago Medical Center

The scientists used single-cell RNA-sequencing to analyze gene expression patterns in peripheral mononuclear blood cells—a distinct set of specialized immune cells that perform vital roles in the body’s response to infection. The researchers gathered these cells from men of European and African ancestry and later exposed the cells to flu in a lab setting.

This enabled the researchers to investigate the gene signatures of different immune cell types and evaluate how infection with the flu virus impacted each cell type’s gene expression.

The researchers noted that people of European ancestry displayed an increase in type I interferon pathway activity at the time of early influenza infection.

Interferons are proteins that are critical for fighting viral infections. In COVID-19, for example, the type I interferon response has been associated with differences in the severity of the disease.”

Luis Barreiro PhD, Study Senior Author and Associate Professor, Medicine, University of Chicago Medical Center

This increased pathway activation was linked with a higher capacity to stop the replication of the virus and a higher capacity to restrict viral replication at a later time point.

Barreiro further states, “Inducing a strong type I interferon pathway response early upon infection stops the virus from replicating and may therefore have a direct impact on the body’s ability to control the virus. Unexpectedly, this central pathway to our defense against viruses appears to be amongst the most divergent between individuals from African and European ancestry.”

The scientists observed numerous differences in gene expression on various cell types, denoting that the immune response variation cannot be isolated to a single type of immune cell, but instead it links to a constellation of cells that function together to combat disease.

A similar difference in immune pathway activation can impart disparities in influenza outcomes between various racial groups. Compared to other racial groups, Non-Hispanic Black Americans are likely to be hospitalized because of the flu.

The scientists are prompt in indicating that these results are not proof of genetic differences in disease susceptibility. Rather various factors like environmental and lifestyle might vary between racial groups and can influence gene expression, which could, in turn, impact the immune response.

Barreiro adds, “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.”

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.”

Luis Barreiro PhD, Study Senior Author and Associate Professor, Medicine, University of Chicago Medical Center

The differences in susceptibility to viral infection might go extend beyond the flu virus. While the scientists compared a list of genes linked to differences in the severity of COVID-19 disease, the majority of the same genes displayed substantial differences in their expression after flu infection between people of European and African ancestry.

“We didn’t study COVID-19 patient samples as part of this study, 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,” concluded Barreiro.

The scientists are analyzing this and other related questions in depth. They anticipate identifying the factors that contribute to the variations in the interferon response and immune responses more widely, to predict individual disease risk.