%0 Journal Article
%T Interferon induced protein 35 exacerbates H5N1 influenza disease through the expression of IL-12p40 homodimer
%A Adrianus C. M. Boon
%A Anshu P. Gounder
%A Brian T. Edelson
%A Christine C. Yokoyama
%A Nicholas N. Jarjour
%A Traci L. Bricker
%J -
%D 2018
%R 10.1371/journal.ppat.1007001
%X 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
%K Influenza A virus
%K Cytokines
%K H5N1
%K Inflammatory diseases
%K Mouse models
%K Immune response
%K Interferons
%K Pathogens
%U https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1007001