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IRF5 promotes influenza-induced inflammatory responses in human iPSC-derived myeloid cells and murine models

Forbester, Jessica L., Clement, Mathew, Wellington, Dannielle, Yeung, Amy, Dimonte, Sandra, Marsden, Morgan, Chapman, Lucy, Coomber, Eve L., Tolley, Charlotte, Lees, Emily, Hale, Christine, Clare, Simon, Udalova, Irina, Dong, Tao, Dougan, Gordon and Humphreys, Ian R. 2020. IRF5 promotes influenza-induced inflammatory responses in human iPSC-derived myeloid cells and murine models. Journal of Virology 94 (9) , e00121-20. 10.1128/JVI.00121-20

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Abstract

Recognition of Influenza A virus (IAV) by the innate immune system triggers pathways that restrict viral replication, activates innate immune cells, and regulates adaptive immunity. However, excessive innate immune activation can exaggerate disease. The pathways promoting excessive activation are incompletely understood, with limited experimental models to investigate mechanisms driving influenza-induced inflammation in humans. Interferon regulatory factor (IRF5) is a transcription factor that plays important roles in induction of cytokines after viral sensing. In an in vivo model of IAV infection, IRF5 deficiency reduced IAV-driven immune pathology and associated inflammatory cytokine production, specifically reducing cytokine-producing myeloid cell populations in Irf5-/- mice, but not impacting type 1 IFN production or virus replication. Using cytometry by time-of-flight (CyTOF), we identified that human lung IRF5 expression was highest in cells of the myeloid lineage. To investigate the role of IRF5 in mediating human inflammatory responses by myeloid cells to IAV, we employed human induced pluripotent stem cells (hIPSCs) with biallelic mutations in IRF5, demonstrating for the first time iPS-derived dendritic cells (iPS-DCs) with biallelic mutations can be used to investigate regulation of human virus-induced immune responses. Using this technology, we reveal that IRF5 deficiency in human DCs, or macrophages, corresponded with reduced virus-induced inflammatory cytokine production, with IRF5 acting downstream of TLR7 and, possibly, RIG-I after viral sensing. Thus, IRF5 acts as a regulator of myeloid cell inflammatory cytokine production during IAV infection in mice and humans, and drives immune-mediated viral pathogenesis independently of type 1 IFN and virus replication.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Publisher: American Society for Microbiology
ISSN: 0022-538X
Date of First Compliant Deposit: 25 February 2020
Date of Acceptance: 13 February 2020
Last Modified: 31 Aug 2020 15:23
URI: http://orca.cf.ac.uk/id/eprint/129930

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