Here, we report that the deletion of an interferon induced gene, Ifi35 (interferon induced protein 35), in mice protects the host from severe morbidity following H5N1 infection. Understanding the role of host genes that enhance inflammation will lead to the identification of therapeutic targets and treatments to help lessen severe disease. Following highly pathogenic H5N1-IAV infection, exaggerated inflammatory responses are detrimental to the host and lead to more disease tipping the balance between protection and pathology. Highly pathogenic influenza A viruses (IAV) are an important human pathogen that cause high mortality and can acquire the ability to cause pandemics. These data establish a role for Ifi35 in modulating cytokine production and exacerbating inflammation during IAV infection. Specific antibody blockade of IL-12p80 ameliorated weight loss and reduced cellular infiltration following H5N1-IAV infection in wild-type mice suggesting that increased levels of IL-12p80 alters the immune response to promote inflammation and IAV disease. Decreased levels of IL-12p40 and its homodimer, IL-12p80, were found in bronchoalveolar lavage fluid of H5N1-IAV infected Ifi35 deficient mice. In addition, Ifi35 deficient primary macrophages produce less IL-12p40 following TLR-3, TLR-4, and TLR-7 stimulation in vitro. Expression of Ifi35 by the hematopoietic cell compartment in bone-marrow chimeric mice contributed to increased immune cell recruitment and IL-12p40 production. Reduced weight loss in Ifi35 -/- mice following H5N1-IAV challenge was associated with reduced cellular infiltration and decreased production of specific cytokines and chemokines including IL-12p40. Here, we show that Ifi35 deficiency leads to reduced morbidity in mouse models of highly pathogenic H5N1- and pandemic H1N1-IAV infection. The host Interferon Induced Protein 35 (Ifi35) has been implicated in increased susceptibility to H5N1-IAV infection. Pro-inflammatory cytokinemia is a hallmark of highly pathogenic H5N1 influenza virus (IAV) disease yet little is known about the role of host proteins in modulating a pathogenic innate immune response.
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March 2023
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