Influenza virus is an important human pathogen that can cause severe disease and death in humans. Highly pathogenic influenza viruses, such as H5N1, induce excessive host responses associated with pro- inflammatory cytokine production, recruitment of innate immune cells and a diminished adaptive immune response. The host proteins involved in this pathogenic response are largely unknown. This information is important and will provide a framework for the rational design of new treatments against pathogenic influenza infection. We have previously identified interferon induced protein 35 (IFI35) as a host gene associated with susceptibility to highly pathogenic H5N1 influenza A virus (2, 3). We now present data showing a direct link between murine IFI35 and exacerbation of influenza-virus induced disease. IFI35 knockout mice infected with the highly pathogenic H5N1 influenza virus recovered more rapidly compared to congenic wild type mice, producing less pro-inflammatory cytokines, such as IL12p40, G-CSF and KC. Correspondingly, bone marrow macrophages derived from IFI35 knockout mice produced significantly less IL12p40 following stimulation with a TLR3 agonist. The IL12p40 is produced as a homodimer (IL12p402) which is a chemo attractant and pre- inflammatory cytokine.In summary, IFI35 appears to be a key regulator of the inflammatory response following viral infection. This proposal is aimed at characterizing how IFI35 protein modulates IL12p40 and IL12p402 production after influenza virus infection and investigating mechanistically how IFI35 shapes the inflammatory environment and disease outcome.

Public Health Relevance

IFI35 is an IFN stimulated gene, which has been implicated in the innate immune response against several viruses. However, its function remains poorly understood. During highly pathogenic H5N1 influenza virus infection, expression of IFI35 exacerbates disease and inflammation. In vitro, IFI35 increases IL12p40 production by macrophages. These novel findings suggest that IFI35 modifies innate immune responses that affect pathogenesis and disease outcome. The importance of pathogenic influenza virus and wealth of immunological data make this an ideal model system to study IFI35 gene function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI118938-02
Application #
9271149
Study Section
Virology - B Study Section (VIRB)
Program Officer
Hauguel, Teresa M
Project Start
2016-05-10
Project End
2021-04-30
Budget Start
2017-05-01
Budget End
2018-04-30
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130