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• W2953977655 abstract "Influenza virus is a common pathogen that mostly causes mild disease but in rare cases may progress to very severe and life-threatening illness. The pathogenesis of severe influenza in otherwise healthy individuals without known predisposing risk factors however, remains largely unknown 1. Influenza virus is predominantly recognized by the immune system through the cytosolic RNA sensor Retinoic acid-inducible gene I (RIG-I) in non-hematopoietic cells such as lung epithelial cells, and by Toll-like receptor (TLR)7 in hematopoietic cells 1. Common for these PRRs is the activation of interferon (IFN) regulatory factor (IRF)3 and IRF7, which are key transcription factors that cooperate in inducing type I (IFN-α/β) and type III (IFN-λ) IFNs in response to virus, which in turn stimulate the production of a whole range of different IFN stimulated genes (ISG)s with antiviral properties 2. The importance of type I and type III IFNs for the control of influenza virus has been highlighted in several murine models, demonstrating significantly increased susceptibility to influenza virus infection and elevated virus titers in mice lacking genes, such as Ifnb, Ifnar1, Stat1 or Ifnlr1 3-5. In addition, several genome-wide association studies have attempted to link host genetics to the susceptibility to severe influenza infection, but these studies have generally been underpowered and without any major findings 6. More recently, autosomal recessive defects in IRF7 and IRF9 were found to cause life-threatening influenza infection in two unrelated children, demonstrating the importance of IRFs in the immune response against influenza virus 7, 8. Here we describe a patient, P1, a 55-year old Caucasian male with severe influenza A virus (IAV) infection, who was heterozygous for a variant in the 3′UTR of the transcription factor IRF3. The variant (c.1576C>T) identified by whole exome sequencing is rare (frequency < 0.001 in gnomAD) and localized within the 3′UTR of IRF3 (Fig. 1A, B and C) in 7 out of 8 splice variants. One of these (IRF3-CL; NM_001197122.1) is placed in the protein sequence and gives rise to an amino acid substitution from proline to serine at position 447. See Supporting Information Table 1 for a complete list of other identified variants. By RT-qPCR we found IRF3 mRNA to be expressed at similar levels in cells from P1 and healthy controls (Fig. 1D). However, Western blotting on PBMC lysates revealed markedly decreased expression of IRF3 protein in P1 compared to controls (Fig. 1E and Supporting Information Fig. 1). These results indicate that the variant in the 3′UTR of IRF3 might affect the translation of IRF3 mRNA into protein, but not IRF3 mRNA stability. Therefore, we performed an in vitro translation analysis relying on HeLa cell lysates which, did however not demonstrate any difference in expression between IRF3 WT or the IRF3 c.1576T variant (Fig. 1F). Moreover, expression of the IRF3 3′UTR variant in HEK293T cells also did not reveal any significant difference in expression of IRF3 protein between the variant and IRF3 WT (data not shown). Next, we examined the induction of IFNs and inflammatory cytokines in peripheral blood mononuclear cells (PBMC)s from P1 and controls by RT-qPCR in response to infection with two different strains of IAV, IAV PR 8 and IAV pdm09, and herpes simplex virus type 1 (HSV-1) for comparison. Strikingly, we found that P1 exhibited impaired and almost abolished induction of IFNA2, IFNB and IFNL1 in response to infection with all three viruses (Fig. 2A–C). The induction of IL6 and TNFA as well as the ISG IFIT1 was selectively impaired in P1 when cells were infected with IAV pdm09, whereas infection of patient PBMCs with IAV PR8 and HSV-1 resulted in normal to increased responses compared to healthy controls (Fig. 2D, Supporting Information Fig. 2A,B)). In addition, PBMCs from P1 and controls were stimulated with different synthetic pathogen-associated molecular patterns (PAMPs). We found that cells from P1 exhibited impaired induction of IFNA2, IFNB, IFNL1, and IFIT1 in response to stimulation with the TLR3 agonist poly(I:C) and the TLR7/8 agonist R848, as well as decreased production of pro-inflammatory cytokines compared to healthy controls (Fig. 2E–H and Supporting Information Fig. 2C,D)). Surprisingly, when transfecting cells with poly(I:C) or dsDNA, agonists that stimulate RIG-I and dsDNA sensors, respectively, cells from P1 exhibited normal to slightly increased expression of IFNs and IFIT1, while production of pro-inflammatory cytokines was normal (Supporting Information Fig. 2E–J). This finding may be due to redundancy between different IRFs in certain cell types. Gene expression analysis of a broad panel of immune genes was performed on patient and healthy control PBMCs left untreated or infected with IAV pdm09 for 6 h using Nanostring technology. Gene expression patterns markedly differed between patient and controls, with the number of significantly differentially expressed genes in patient cells being much lower than those of controls (29 genes in patient samples versus 157 and 142 genes in each control, respectively) (Fig. 2I). Importantly, 89 genes, encoding both innate and adaptive immune mediators, were only significantly up- or down-regulated in controls (Fig. 2I,J). Most notably, expression of both IFNA2 and IFNB was almost completely abolished in patient cells, whereas IFNG expression was decreased to a lesser degree (Fig. 2J). A STRING analysis further revealed a large degree of interconnection and functional diversity of the upregulated genes (Supporting Information Fig. 3B). Finally, IRF7 failed to be upregulated upon IAV infection in P1 compared to controls (Supporting Information Fig. 3C). IRFs are key transcription factors that regulate the induction of IFNs 2. The first and only case of IRF3 deficiency so far was reported by Andersen et. al in a study from 2015, demonstrating a heterozygous missense variant in the regulatory domain of IRF3 causing decreased transcription factor activity and increased susceptibility to herpes simplex encephalitis (HSE) in an adolescent 9. Subsequently, IRF7- and IRF9 deficiencies were identified in two unrelated children with severe disseminated influenza infection, adding to the evidence suggesting an important role of IRFs and IFN in immunity against influenza virus infection 7, 8. More recently, a genetic variant in the cytosolic RNA sensor RIG-I has been identified in an adult patient presenting with severe disseminated influenza infection 10. Here, we report the identification of a variant of the transcription factor IRF3 together with impaired antiviral IFN responses in an adult patient who developed severe life-threatening influenza infection during the H1N1 swine flu pandemic in 2009–2010. We favor a scenario, in which the identified IRF3 3′UTR variant exerts an effect by haploinsufficiency rather than by a dominant negative effect, since the coding region of IRF3 is normal, wherefore any translated protein most likely would function and signal normally. The IRF3-CL transcript variant is believed to function as a negative regulator of the remaining IRF3 transcripts, and a missense variant herein is therefore unlikely to explain the infectious and immunological phenotype. The mechanism, whereby this variant causes less IRF3 protein expression and impaired antiviral responses, thus remains incompletely understood, given that IRF3 mRNA levels were found to be normal in patient PBMCs, and in vitro translation of the IRF3 variant was comparable to WT IRF3. However, the in vitro translation assay may not precisely reflect the physiological situation, since IRF3 protein expression was markedly reduced in cell lysates from patient PBMCs. In summary, the present report is in line with previous studies demonstrating a central role of this family of transcription factors in inducing potent and immediate IFN responses in antiviral immunity to IAV in humans. We would like to thank the patient for participation in the study. THM received funding from Aarhus University Research Foundation (AUFF-E-215-FLS-8-66), the Danish Council for Independent Research-Medical Sciences (# 4004-00047B), and The Lundbeck Foundation (R268-406 2016–3927). RH was funded by the Danish Council for Independent Research-Medical Sciences (7016-00331). The authors declare no financial or commercial conflict of interest. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article." @default.
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• W2953977655 date "2019-11-01" @default.
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• W2953977655 title "Identification of an <i>IRF3</i> variant and defective antiviral interferon responses in a patient with severe influenza" @default.
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• W2953977655 doi "https://doi.org/10.1002/eji.201848083" @default.
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