Influenza virus replication in cardiomyocytes drives heart dysfunction and fibrosis

Adam D. Kenney, Stephanie L. Aron, Clara Gilbert, Naresh Kumar, Peng Chen, Adrian Eddy, Lizhi Zhang, Ashley Zani, Nahara Vargas-Maldonado, Samuel Speaks, Jeffrey Kawahara, Parker J. Denz, Lisa Dorn, Federica Accornero, Jianjie Ma, Hua Zhu, Murugesan V.S. Rajaram, Chuanxi Cai, Ryan A. Langlois, Jacob S. Yount

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

Cardiac dysfunction is a common complication of severe influenza virus infection, but whether this occurs due to direct infection of cardiac tissue or indirectly through systemic lung inflammation remains unclear. To test the etiology of this aspect of influenza disease, we generated a novel recombinant heart-attenuated influenza virus via genome incorporation of target sequences for miRNAs expressed in cardiomyocytes. Compared with control virus, mice infected with miR-targeted virus had significantly reduced heart viral titers, confirming cardiac attenuation of viral replication. However, this virus was fully replicative in the lungs and induced similar systemic inflammation and weight loss compared to control virus. The miR-targeted virus induced fewer cardiac conduction irregularities and significantly less fibrosis in mice lacking interferon-induced transmembrane protein 3 (IFITM3), which serve as a model for influenza-associated cardiac pathology. We conclude that robust virus replication in the heart is required for pathology, even when lung inflammation is severe.

Original languageEnglish (US)
Article numbereabm5371
JournalScience Advances
Volume8
Issue number19
DOIs
StatePublished - May 2022

Bibliographical note

Funding Information:
This research was supported by NIH grants AI130110, AI151230, and AI142256 to J.S.Y.; grant AI146252 to M.V.S.R.; grants AI148669 and AI132962 to R.A.L.; grant HL154001 to J.S.Y. and F.A.; and grant AI146690 to J.S.Y. and M.V.S.R. A.D.K. was supported by The Ohio State University Systems and Integrative Biology Training Program funded by NIH grant GM068412 and The Ohio State University Presidential Fellowship. A.Z. and A.E. were supported by an Ohio State University Infectious Diseases Institute training grant funded by NIH grant AI112542 and The Ohio State University College of Medicine. A.Z. was also funded by the National Science Foundation GRFP Fellowship.

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