Interferon induced protein 35 exacerbates H5N1 influenza disease through the expression of IL-12p40 homodimer

• Published in: PLoS pathogens 2018-04, Vol.14 (4), p.e1007001-e1007001
• Main Authors: Gounder, Anshu P, Yokoyama, Christine C, Jarjour, Nicholas N, Bricker, Traci L, Edelson, Brian T, Boon, Adrianus C M
• Format: Article
• Language: English
• Subjects: Alveoli; Analysis; Animal models; Animals; Avian flu; Avian influenza; Binding sites; Biology and life sciences; Bone marrow; Bronchus; Cellular manufacture; Chemokines; Chemokines - metabolism; Cytokines; Cytokines - metabolism; Dimerization; Female; Funding; Gene expression; Genetic aspects; Immune response; Immune system; Immunity, Innate - immunology; Immunology; Infections; Infiltration; Inflammation; Influenza; Influenza A Virus, H5N1 Subtype - pathogenicity; Innate immunity; Interferon; Interleukin 12; Interleukin-12 Subunit p40 - chemistry; Interleukin-12 Subunit p40 - metabolism; Internal medicine; Intracellular Signaling Peptides and Proteins - physiology; Macrophages; Male; Medicine; Medicine and health sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Morbidity; Orthomyxoviridae Infections - metabolism; Orthomyxoviridae Infections - pathology; Orthomyxoviridae Infections - virology; Pandemics; Pathology; Pneumonia - metabolism; Pneumonia - pathology; Pneumonia - virology; Proteins; Research and Analysis Methods; Rodents; Scholarships & fellowships; Viruses; Weight loss; Weight reduction
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1007001

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.