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Edited by Peter Palese, Icahn School of Medicine at Mount Sinai, New York, NY, and approved August 1, 2019 (received for review January 15, 2019)
Significance
We discovered that IFITM3 prevents efficient dissemination and replication of influenza virus in heart tissue, thereby limiting cardiac fibrosis and electrical dysfunction during infection. Since IFITM3 polymorphisms are among the only human genetic factors that have been reproducibly associated with hospitalization and mortality during influenza virus infection, our findings are relevant to the serious threat of influenza virus infection to human health. Furthermore, IFITM3 KO mice provide one of the first models for studying cardiac complications of influenza.
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.
Footnotes
- ↵1To whom correspondence may be addressed. Email: murugesan.rajaram{at}osumc.edu or Jacob.Yount{at}osumc.edu.
Author contributions: A.D.K., M.V.S.R., and J.S.Y. designed research; A.D.K., T.M.M., A.I., N.M.C., L.Z., L.E.D., Q.W., O.A., A.Z., M. Chemudupati, F. Accornero, M.V.S.R., and J.S.Y. performed research; F. Amari, M. Chen, and V.C. contributed new reagents/analytic tools; A.D.K., T.M.M., N.M.C., M.V.S.R., and J.S.Y. analyzed data; and A.D.K. and J.S.Y. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1900784116/-/DCSupplemental.
Published under the PNAS license.
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IFITM3 protects the heart during influenza virus infection
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