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IFITM3 protects the heart during influenza virus infection

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  • IFITM3 protects the heart during influenza virus infection

    Proc Natl Acad Sci U S A. 2019 Aug 26. pii: 201900784. doi: 10.1073/pnas.1900784116. [Epub ahead of print]
    IFITM3 protects the heart during influenza virus infection.

    Kenney AD1,2, McMichael TM1, Imas A1, Chesarino NM1, Zhang L1,2, Dorn LE3, Wu Q1, Alfaour O1, Amari F4, Chen M4, Zani A1,2, Chemudupati M1,2, Accornero F2,3, Coppola V2,4,5, Rajaram MVS6,2, Yount JS6,2.
    Author information

    1 Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH 43210. 2 Infectious Diseases Institute, The Ohio State University, Columbus, OH 43210. 3 Department of Physiology and Cell Biology, The Ohio State University, Columbus, OH 43210. 4 Genetically Engineered Mouse Modeling Core, The Ohio State University and James Comprehensive Cancer Center, Columbus, OH 43210. 5 Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH 43210. 6 Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH 43210; murugesan.rajaram@osumc.edu Jacob.Yount@osumc.edu.

    Abstract

    Influenza virus can disseminate from the lungs to the heart in severe infections and can induce cardiac pathology, but this has been difficult to study due to a lack of small animal models. In humans, polymorphisms in the gene encoding the antiviral restriction factor IFN-induced transmembrane protein 3 (IFITM3) are associated with susceptibility to severe influenza, but whether IFITM3 deficiencies contribute to cardiac dysfunction during infection is unclear. We show that IFITM3 deficiency in a new knockout (KO) mouse model increases weight loss and mortality following influenza virus infections. We investigated this enhanced pathogenesis with the A/PR/8/34 (H1N1) (PR8) influenza virus strain, which is lethal in KO mice even at low doses, and observed increased replication of virus in the lungs, spleens, and hearts of KO mice compared with wild-type (WT) mice. Infected IFITM3 KO mice developed aberrant cardiac electrical activity, including decreased heart rate and irregular, arrhythmic RR (interbeat) intervals, whereas WT mice exhibited a mild decrease in heart rate without irregular RR intervals. Cardiac electrical dysfunction in PR8-infected KO mice was accompanied by increased activation of fibrotic pathways and fibrotic lesions in the heart. Infection with a sublethal dose of a less virulent influenza virus strain (A/WSN/33 [H1N1]) resulted in a milder cardiac electrical dysfunction in KO mice that subsided as the mice recovered. Our findings reveal an essential role for IFITM3 in limiting influenza virus replication and pathogenesis in heart tissue and establish IFITM3 KO mice as a powerful model for studying mild and severe influenza virus-induced cardiac dysfunction.


    KEYWORDS:

    IFITM3; heart; influenza; interferon

    PMID: 31451661 DOI: 10.1073/pnas.1900784116
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