SNP-mediated disruption of CTCF binding at the IFITM3 promoter is associated with risk of severe influenza in humans

Abstract

Previous studies reported associations of IFITM3 SNP rs12252 with severe influenza, but evidence of association and the mechanism of risk remains controversial. We prioritized SNPs in IFITM3 based on putative biological function and identified rs34481144 in the 5′ UTR. We found evidence of a novel association of rs34481144 with severe influenza in three influenza-infected cohorts characterized by different levels of influenza illness severity. We determined the role of rs34481144 as an expression quantitative trait loci (eQTL) for IFITM3, with the risk allele associated with lower mRNA expression. The risk allele was found to have decreased IRF3 binding and increased CTCF binding in promoter-binding assays, and risk allele carriage diminished transcriptional correlations among neighboring genes, indicative of CTCF boundary activity. Furthermore, the risk allele disrupts a CpG site that undergoes differential methylation in CD8 T-cell subsets. Carriers of the risk allele had reduced CD8 T-cells in their airways during natural influenza infection, consistent with IFITM3 promoting airway CD8 T-cell accumulation, indicating that a critical function for IFITM3 may be to promote immune cell persistence at mucosal sites. Our study identifies a new regulator of IFITM3 expression that associates with CD8 T-cell levels in the airways and a spectrum of clinical outcomes.

Host Single Nucleotide Polymorphisms Modulating Influenza A Virus Disease in Humans

“…Another important SNP (rs34481144) associated with risk of severe influenza in humans from the United States (US) infected with seasonal IAVs is located in the 5 -UTR of the IFITM3 gene [123,124]. This SNP affected IFITM3 expression being the risk allele associated with lower mRNA expression.…”

“…This SNP affected IFITM3 expression being the risk allele associated with lower mRNA expression. The mechanism for this lower mRNA expression involves the decreased IRF-3 binding and increased binding of the transcriptional repressor CCCTC-binding factor (CTCF) in promoter-binding assays for the risk allele [123]. Moreover, the risk allele disrupted a CpG site that becomes differentially methylated in CD8+ T cell subsets, leading to less CD8+ T cells in the airways during natural influenza infection in the carriers of the risk allele, and suggesting that a critical role for IFITM3 may be to promote immune cell persistence at mucosal sites [123].…”

Rapid interferon independent expression of IFITM3 following T cell activation protects cells from influenza virus infection

“…IFITM3 is particularly effective at protecting against influenza virus infection and the absence of this single antiviral protein is associated with exacerbated influenza infection in both mice and humans [1,4,5]. As such, IFITM3 knockout mice succumb to sublethal doses of influenza virus [3,6] and humans expressing a functionally defective IFITM3 allelic variant are more prone to severe influenza virus infection [7][8][9][10]. IFITM3 inhibits viral entry, the earliest step of the a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 virus life cycle, by preventing viruses from traversing the lipid bilayer of the cell and accessing the cytoplasm [11].…”

“…We have previously reported that dendritic cells stationed within the lung upregulate IFITM3 following influenza virus infection, a process driven by exposure to type I interferon, and this was crucial for these cells to successfully traffic influenza viral antigen from the lung to draining lymph node (LN) without becoming infected and perishing en route [23]. Tissue resident memory T cells in the airways [10], lung [17], skin [24] and brain [25] constitutively express IFITM3, and this is associated with enhanced resistance to viral infection and therefore long-term survival within peripheral tissues.…”

Calculated risk: a new single-nucleotide polymorphism linked to severe influenza disease

“…Host genetic factors have emerged as potential regulators of human influenza disease susceptibility, and may explain severe disease in otherwise apparently healthy individuals. In this issue of Nature Medicine , Allen et al reveal a new single nucleotide polymorphism (SNP) risk allele in the IFITM3 gene that is strongly associated with severe influenza disease, and further detail a novel mechanism through which this SNP regulates IFITM3 expression to influence survival of CD8 + T lymphocytes (CTLs) (Figure 1) 2 .…”