{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T05:06:41Z","timestamp":1790053601680,"version":"4.0.1"},"reference-count":60,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T00:00:00Z","timestamp":1789862400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["P51OD011104-62"],"award-info":[{"award-number":["P51OD011104-62"]}]},{"name":"NIH","award":["AHA962950"],"award-info":[{"award-number":["AHA962950"]}]},{"name":"NIH","award":["R01DK129881"],"award-info":[{"award-number":["R01DK129881"]}]},{"name":"NIH","award":["R01HL165265"],"award-info":[{"award-number":["R01HL165265"]}]},{"name":"NIH","award":["1F31AI191758-01"],"award-info":[{"award-number":["1F31AI191758-01"]}]},{"name":"Tulane start-up funds"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Influenza A virus (IAV) remains a major cause of respiratory morbidity and mortality worldwide. However, the precise role of the RNA sensor Toll-like receptor 7 (TLR7) and its downstream signaling mediator, interferon regulatory factor 7 (IRF7), during IAV infection remains elusive. To address this gap, we utilized single-cell RNA sequencing (scRNA-seq) alongside Tlr7-deficient and Irf7-deficient mouse models infected with the mouse-adapted IAV strain PR8. Pulmonary scRNA-seq of PR8-infected wild-type mice revealed robust upregulation of Tlr7 and interferon (IFN) pathway-associated genes specifically in dendritic cells (DCs) and B cells, whereas Irf7 induction occurred globally across all major lung compartments. Following PR8 infection, Irf7-deficient but not Tlr7-deficient mice exhibited significantly greater daily weight loss, increased mortality, and more severe bronchial epithelial hyperplasia compared to wild-type controls. Furthermore, infected Irf7-deficient mice displayed diminished early IFN-\u03b1 and IFN-\u03b3 levels. Interestingly, both Irf7- and Tlr7-deficient strains demonstrated impaired anti-hemagglutinin (HA) antibody production. Notably, Tlr7 deficiency did not alter Irf7 protein expression or the production of IFNs and NF-\u03baB in response to IAV, indicating that Tlr7 does not modulate Irf7 activation during infection. Collectively, these findings demonstrate that Irf7 protects against severe IAV pathogenesis independently of Tlr7 recognition in mice, whereas both Irf7 and Tlr7 are required for optimal anti-HA antibody production. Importance: Influenza A virus is a respiratory pathogen that remains a major threat to global health as a seasonal disease and a source of periodic pandemics. The outcomes of the infection can range from mild illness to severe pneumonia and death, particularly in vulnerable populations, yet the reasons why some individuals develop more severe disease are not fully understood. Early immune defenses in the lungs are critical for controlling the virus, but they can also contribute to harmful inflammation if not properly regulated. Key sensors that detect viral genetic material, such as TLR7, and the signaling pathways that activate antiviral responses, such as IRF7, play an essential role in shaping these outcomes. However, whether TLR7 is essential or redundant in IAV remains debated, and the independent role of IRF7 in IAV has not been directly demonstrated in mouse models. The significance of our study lies in defining how these early immune mechanisms influence the course of influenza A infection, providing insight that may guide the development of improved therapies for influenza and related respiratory viruses.<\/jats:p>","DOI":"10.3390\/v18091042","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T08:03:47Z","timestamp":1789977827000},"page":"1042","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["IRF7 Protects Against Severe Influenza A Infection Independently of TLR7 Recognition in Mice"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-6952-4278","authenticated-orcid":false,"given":"Ana Karina","family":"Nisperuza Vidal","sequence":"first","affiliation":[{"name":"Division of Comparative Pathology, Tulane National Biomedical Research Center, Covington, LA 70433, USA"},{"name":"Department of Microbiology 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USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaofeng","family":"Ding","sequence":"additional","affiliation":[{"name":"Division of Comparative Pathology, Tulane National Biomedical Research Center, Covington, LA 70433, USA"},{"name":"Department of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, LA 70112, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"}]},{"given":"Jefferson","family":"Fernandes Evangelista","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, LA 70112, 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Medicine, New Orleans, LA 70112, USA"},{"name":"Department of Pulmonary Critical Care and Environmental Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Micaela R.","family":"Boxer Wachler","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, LA 70112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7111-525X","authenticated-orcid":false,"given":"Calder R.","family":"Ellsworth","sequence":"additional","affiliation":[{"name":"Division of Comparative Pathology, Tulane National Biomedical Research Center, Covington, LA 70433, USA"},{"name":"Department of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, LA 70112, 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