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PLoS Pathog. 2018 Apr 26;14(4):e1007001. doi: 10.1371/journal.ppat.1007001. eCollection 2018 Apr.

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

Author information

1
Department of Internal Medicine, Washington University in Saint Louis School of Medicine, St. Louis, MO, United States of America.
2
Department of Molecular Microbiology, Washington University in Saint Louis School of Medicine, St. Louis, MO, United States of America.
3
Department of Pathology and Immunology, Washington University in Saint Louis School of Medicine, St. Louis, MO, United States of America.

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.

PMID:
29698474
PMCID:
PMC5940246
DOI:
10.1371/journal.ppat.1007001
[Indexed for MEDLINE]
Free PMC Article

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