Deletion of <b><i>Irf3</i></b> and <b><i>Irf7</i></b> Genes in Mice Results in Altered Interferon Pathway Activation and Granulocyte-Dominated Inflammatory Responses to Influenza A Infection

Abstract

The interferon (IFN) pathway plays an essential role in the innate immune response following viral infections and subsequent shaping of adaptive immunity. Infections with influenza A viruses (IAV) activate the IFN pathway after the recognition of pathogen-specific molecular patterns by respective pattern recognition receptors. The IFN regulatory factors IRF3 and IRF7 are key players in the regulation of type I and III IFN genes. In this study, we analyzed the role of IRF3 and IRF7 for the host response to IAV infections in Irf3^-/-, Irf7^-/-, and Irf3^-/-Irf7^-/- knockout mice. While the absence of IRF3 had only a moderate impact on IFN expression, deletion of IRF7 completely abolished IFNα production after infection. In contrast, lack of both IRF3 and IRF7 resulted in the absence of both IFNα and IFNβ after IAV infection. In addition, IAV infection of double knockout mice resulted in a strong increase of mortality associated with a massive influx of granulocytes in the lung and reduced activation of the adaptive immune response.

Knockout of IRF7 Highlights its Modulator Function of Host Response Against Avian Influenza Virus and the Involvement of MAPK and TOR Signaling Pathways in Chicken

“…In this perspective, the upregulation of the MAPK pathway in the IRF7 -/cells could possibly explain the increased viral replication phenotype of the IRF7 KO cells. Our observations were in line with the study comparing transcriptomes between the wildtype and Irf3 -/-Irf7 -/double KO (DKO) mice infected with PR8 (H1N1), in which the upregulation of MAPK signaling pathway was observed to correlate with susceptible phenotypes of mutants such as significant weight loss, a higher mortality and a higher viral load with infection [43]. A validation of the chicken IRF7 KO susceptibility phenotype against AIV at a systemic level is warranted to elucidate the underlying molecular mechanism.…”

“…We also demonstrated that the deletion of IRF7 resulted in the higher replication of LPAIVs in vitro, which further suggests an anti-viral role of IRF7 in chickens. This phenotype was in agreement with the susceptible phenotype observed in Irf7 -/mice against viral infections (herpes simplex virus, encephalomyocarditis virus or influenza virus) [10,43]. Functional enrichment of DEGs contrasting between IRF7 wt and IRF7 -/cells identified the MAPK pathway as one of the significant pathways altered due to IRF7 KO ( Figure 2D).…”

“…Particularly, the constant augmentation of transcription factor NF-κB (nuclear factor kappa B; subunit RELA, inhibitor NFKBIB) and AP1 (activator protein 1; subunit FOS) expression during infection due to IRF7 deletion suggests that these factors complement IRF7 in the host antiviral response by modulating inflammatory cytokines and type I IFNs in chickens, as in mammals ( Figure 5D, Figure S3) [52]. This is in line with the observation from a Irf3 -/-Irf7 -/-(DKO) mice study in which the DKO mice displayed impaired interferon activation and an increased inflammatory response upon influenza A virus infection [43]. In addition, Irf3 -/-Irf7 -/-DKO mice as well as Irf3 -/-Irf5 -/-Irf7 -/triple KO mice infected with dengue virus had demonstrated enriched inflammatory process-related genes at 24 hpi compared to the wildtype animals [53].…”

Attenuation of interferon regulatory factor 7 activity in local infectious sites of trachea and lung for preventing the development of acute lung injury caused by influenza A virus

“…The exiting IRF7 can be activated immediately and therefore induces IFN‐ α rapidly in response to viral infection . Evidently, IRF7 is the master regulator of IFN‐ α , because the deletion of IRF3 can partially reduce the production of IFN‐ α and IFN‐ β , whereas the deletion of IRF7 can completely abolish the production of IFN‐ α but only partially reduce the production of IFN‐ β . IRF7 deficiency is positively correlated with the susceptibility of severe and life‐threatening IAV infection .…”

“…29 Evidently, IRF7 is the master regulator of IFN-a, because the deletion of IRF3 can partially reduce the production of IFN-a and IFN-b, whereas the deletion of IRF7 can completely abolish the production of IFN-a but only partially reduce the production of IFN-b. 30,31 IRF7 deficiency is positively correlated with the susceptibility of severe and life-threatening IAV infection. 32 However, reports reveal that the excessive expression of IRF7 can increase the disease severity of systemic lupus erythematosus and serum levels of IFN-a in patients with systemic lupus erythematosus.…”