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.
Highlights
Respiratory viruses with pandemic potential pose enormous health and economic impacts on the human population
We found that bystander cells display increased mRNA expression of IFN stimulated genes (ISGs) relative to infected cells; yet, we observed both an induction of ribosomal gene mRNA expression in influenza A viruses (IAV)-transcribing cells and a down regulation of these genes in bystander cells at later time points
While the former is likely induced by the virus to enhance mRNA translation [33], the repression of ribosomal expression observed in bystander cells may reflect a host mechanism to contain infection by shutting down the translational machinery of neighboring cells, and we speculate that this may hold true across other cells types and constitute a general cellular defense mechanism against viral infections
Summary
Respiratory viruses with pandemic potential pose enormous health and economic impacts on the human population. A harrowing and shared feature of these pandemics are the sudden deaths of otherwise healthy individuals [1]. Sentinel cells such as lung-resident macrophages trigger complex signaling cascades that recruit leukocytes to the site of infection, among them monocytes. These infiltrating monocytes differentiate into monocyte-derived dendritic cells or macrophages, enabling viral clearance through the induction of the adaptive response, and help replenish the pool of tissue-resident alveolar macrophages [4, 7]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
