Abstract
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. The host Interferon Induced Protein 35 (Ifi35) has been implicated in increased susceptibility to H5N1-IAV infection. Here, we show that Ifi35 deficiency leads to reduced morbidity in mouse models of highly pathogenic H5N1- and pandemic H1N1-IAV infection. 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. Expression of Ifi35 by the hematopoietic cell compartment in bone-marrow chimeric mice contributed to increased immune cell recruitment and IL-12p40 production. In addition, Ifi35 deficient primary macrophages produce less IL-12p40 following TLR-3, TLR-4, and TLR-7 stimulation in vitro. Decreased levels of IL-12p40 and its homodimer, IL-12p80, were found in bronchoalveolar lavage fluid of H5N1-IAV infected Ifi35 deficient mice. 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. These data establish a role for Ifi35 in modulating cytokine production and exacerbating inflammation during IAV infection.
Highlights
Infections with highly pathogenic influenza virus (IAV), such as H5N1-IAV, are characterized by high viral titers, excessive inflammation, and increased mortality after infection [1,2,3]; (WHO/GIP, 2017)
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
Interferon Induced Protein 35 (Ifi35) deficiency leads to reduced weight loss following IAV infection
Summary
Infections with highly pathogenic IAV, such as H5N1-IAV, are characterized by high viral titers, excessive inflammation, and increased mortality after infection [1,2,3]; (WHO/GIP, 2017). The relative contributions of virus replication and immunopathology in driving severe disease remain unclear and have fundamental implications in treating H5N1-IAV infections. Increased levels of the cytokines IL-6, IL-10, and IL-12 as well as the chemokines CXCL10 and CXCL2 have been reported to contribute to immune dysregulation and severe disease following H5N1 infection in humans and mice [9,10,11,12]. Several studies have suggested pathogenic roles for IFN and IFN-induced host proteins during IAV infection [13,14,15,16]. Modulation of cytokine production and IFN signaling needs to be balanced to control virus infection but not promote excessive inflammation and immunopathology. The role of host proteins in regulating this balance of innate immune responses to IAV infection is not well characterized
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