Interferon Regulatory Factors IRF1 and IRF7 Directly Regulate Gene Expression in Bats in Response to Viral Infection

• Published in: Cell reports (Cambridge) Vol. 33; no. 5; p. 108345
• Main Authors: Irving, Aaron T., Zhang, Qian, Kong, Pui-San, Luko, Katarina, Rozario, Pritisha, Wen, Ming, Zhu, Feng, Zhou, Peng, Ng, Justin H.J., Sobota, Radoslaw M., Wang, Lin-Fa
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03.11.2020; The Author(s); Elsevier
• Subjects: Animals; bat; Chiroptera - immunology; Gene Expression Regulation - immunology; Herpesvirus 1, Human - immunology; IAV; Influenza A virus - immunology; innate immunity; interferon; Interferon Regulatory Factor; Interferon Regulatory Factor-1 - immunology; Interferon Regulatory Factor-7 - immunology; IRF; IRG; MERS; Middle East Respiratory Syndrome Coronavirus - immunology; Orthoreovirus - immunology; PRV3M; virus; Virus Diseases - immunology; Interferon Regulatory Factor; PRV3M; bat; innate immunity; IRF; interferon; MERS; virus; IAV; IRG
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2020.108345

Bat cells and tissue have elevated basal expression levels of antiviral genes commonly associated with interferon alpha (IFNα) signaling. Here, we show Interferon Regulatory Factor 1 (IRF1), 3, and 7 levels are elevated in most bat tissues and that, basally, IRFs contribute to the expression of type I IFN ligands and high expression of interferon regulated genes (IRGs). CRISPR knockout (KO) of IRF 1/3/7 in cells reveals distinct subsets of genes affected by each IRF in an IFN-ligand signaling-dependent and largely independent manner. As the master regulators of innate immunity, the IRFs control the kinetics and maintenance of the IRG response and play essential roles in response to influenza A virus (IAV), herpes simplex virus 1 (HSV-1), Melaka virus/Pteropine orthoreovirus 3 Melaka (PRV3M), and Middle East respiratory syndrome-related coronavirus (MERS-CoV) infection. With its differential expression in bats compared to that in humans, this highlights a critical role for basal IRF expression in viral responses and potentially immune cell development in bats with relevance for IRF function in human biology. [Display omitted] •IRF1, 3, and 7 are highly expressed in multiple bat tissues and control gene expression•Antiviral IRG expression in bat cells is largely IFN independent•IRF1 and 7 regulate distinct subsets and alter the kinetics/maintenance of IRGs•IRF1, 3, and 7 regulate antiviral responses to IAV/MERS/HSV-1/PRV3M in bat cells Bats express high levels of antiviral genes in response to synthetic dsRNA, IFN, or virus by the transcription factors IRF1/3/7. Irving et al. show that this induction largely bypasses IFNα/β production and that this may be a method for limiting the inflammation induced by IFN signaling while still restricting virus infection.