Single-cell genome-wide association reveals that a nonsynonymous variant in ERAP1 confers increased susceptibility to influenza virus

Shaping immunity: The influence of natural selection on population immune diversity

“…Indeed, multiple studies have successfully leveraged in vitro infection models to identify transcriptional variation in the immune responses to pathogens across individuals of different genetic ancestries. [16][17][18][19][20] Two flagship studies focusing on the transcriptional profiles of monocytes and macrophages uncovered thousands of genes displaying a significant divergence in the intensity of the response to various pathogens, including Listeria monocytogenes, Salmonella typhimurium, and influenza A virus (IAV), between African and European ancestry individuals in independent cohorts. 16,17,21 Of note, a greater proportion of global African ancestry was associated with a stronger proinflammatory response to bacterial challenge, and individuals with increased African ancestry were also better able to control intracellular bacterial growth in macrophages compared to individuals with increased European ancestry, highlighting the potential functional consequences of the observed response variation.…”

“…In particular, various studies have turned to single-cell RNAsequencing of peripheral blood mononuclear cells (PBMCs) to measure genetic ancestry effects in the context of viral infections. [18][19][20]22 Because PBMCs are comprised of multiple, distinct immune cell types, single-cell methods can dissect independent signals from each cell population within the same experiment. Across cell types, genetic ancestry effects on gene expression were found to be highly cell type-specific, with the majority of effects only detected in one or two cell types.…”

“…One common missense variant in ERAP1, rs27895, has been shown to increase IAV burden in lymphoblastoid cell lines in vitro, which was replicated in a human influenza challenge study in vivo, and is known to exhibit population differentiation globally. 19 The ancestral C allele of rs27895, which is associated with IAV resistance, is nearly fixed in East Asian populations, whereas the derived T allele is more common throughout the rest of the world (minor allele frequency, MAF = 6.4% in European populations and 23.8% in African populations in the 1000 Genomes Project 48 ). Indeed, cell lines from populations with a higher frequency of the C allele are more protected from IAV in vitro, suggesting this variant has a functional consequence and may play a role in mediating population differences in susceptibility to viral infection.…”

“…Indeed, cell lines from populations with a higher frequency of the C allele are more protected from IAV in vitro, suggesting this variant has a functional consequence and may play a role in mediating population differences in susceptibility to viral infection. 19…”

“…In vitro challenge studies of primary immune cells or cell lines obtained from individuals with varying genetic ancestry backgrounds represent a powerful approach to measure population differences in the immune response to infection (Figure 1). Indeed, multiple studies have successfully leveraged in vitro infection models to identify transcriptional variation in the immune responses to pathogens across individuals of different genetic ancestries 16–20 . Two flagship studies focusing on the transcriptional profiles of monocytes and macrophages uncovered thousands of genes displaying a significant divergence in the intensity of the response to various pathogens, including Listeria monocytogenes , Salmonella typhimurium , and influenza A virus (IAV), between African and European ancestry individuals in independent cohorts 16,17,21 .…”