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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chemokines / metabolism
  • Cytokines / metabolism
  • Dimerization
  • Female
  • Immunity, Innate / immunology*
  • Influenza A Virus, H5N1 Subtype / pathogenicity*
  • Interleukin-12 Subunit p40 / chemistry
  • Interleukin-12 Subunit p40 / metabolism*
  • Intracellular Signaling Peptides and Proteins / physiology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Orthomyxoviridae Infections / metabolism
  • Orthomyxoviridae Infections / pathology
  • Orthomyxoviridae Infections / virology*
  • Pneumonia / metabolism
  • Pneumonia / pathology
  • Pneumonia / virology*


  • Chemokines
  • Cytokines
  • IFP35 protein, mouse
  • Interleukin-12 Subunit p40
  • Intracellular Signaling Peptides and Proteins