Single-Cell and Bulk RNA-Sequencing Reveal Differences in Monocyte Susceptibility to Influenza A Virus Infection Between Africans and Europeans

Abstract

There is considerable inter-individual and inter-population variability in response to viruses. The potential of monocytes to elicit type-I interferon responses has attracted attention to their role in viral infections. Here, we use single-cell RNA-sequencing to characterize the role of cellular heterogeneity in human variation of monocyte responses to influenza A virus (IAV) exposure. We show widespread inter-individual variability in the percentage of IAV-infected monocytes. Notably, individuals with high cellular susceptibility to IAV are characterized by a lower activation at basal state of an IRF/STAT-induced transcriptional network, which includes antiviral genes such as IFITM3, MX1 and OAS3. Upon IAV challenge, we find that cells escaping viral infection display increased mRNA expression of type-I interferon stimulated genes and decreased expression of ribosomal genes, relative to both infected cells and those never exposed to IAV. We also uncover a stronger resistance of CD16+ monocytes to IAV infection, together with CD16+-specific mRNA expression of IL6 and TNF in response to IAV. Finally, using flow cytometry and bulk RNA-sequencing across 200 individuals of African and European ancestry, we observe a higher number of CD16+ monocytes and lower susceptibility to IAV infection among monocytes from individuals of African-descent. Based on these data, we hypothesize that higher basal monocyte activation, driven by environmental factors and/or weak-effect genetic variants, underlies the lower cellular susceptibility to IAV infection of individuals of African ancestry relative to those of European ancestry. Further studies are now required to investigate how such cellular differences in IAV susceptibility translate into population differences in clinical outcomes and susceptibility to severe influenza.

Environmental and genetic drivers of population differences in SARS-CoV-2 immune responses

“…Furthermore, variation in innate immunity 8–10 – including inborn errors or neutralizing auto-antibodies against type I interferons 11–13 – contribute to the various SARS-CoV-2-related clinical manifestations, and epidemiological and genetic data suggest differences in the outcome of SARS-CoV-2 infection between populations 6,7,14,15 . These observations, together with previous reports on the importance of ancestry-related differences in transcriptional responses to immune challenges 16–19 , highlight the need for in-depth investigations of the magnitude of variation in immune responses to SARS-CoV-2 and its drivers across populations worldwide.…”

“…7a, b). Individuals of African ancestry also presented higher proportions of CD16 + monocytes 19 and memory lymphocyte subsets, such as memory B cells, effector CD4 + T cells and effector memory CD8 + T cells re-expressing CD45RA (CD8 + EMRA T cells) (Wilcoxon rank-sum p -value < 4.1 × 10 -5 ).…”

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

“…This is consistent with a previous study using scRNA-seq of IAV-infected cells to link basal expression to susceptibility to infection. 30 In summary, in a single infection, we deconvoluted cells from 48 different individuals and observed highly variable flu burden and transcriptional phenotypes. These methods revealed that baseline IFN levels contribute to resistance against influenza infection.…”

Transposable elements are associated with the variable response to influenza infection

“…Moreover, the amount of viral reads observed in the macrophages post-infection can be used as a surrogate for viral load (Thorburn et al, 2015). Indeed, in a similar experimental system this metric was shown to be stable and reproducible across individuals (O’Neill et al, 2021). Notably, by studying the infected macrophages from these 39 individuals, we observed extensive variation in the levels of viral reads and discovered a set of TEs displaying high inter-individual variability in chromatin accessibility following infection.…”