4.8 Article

Influenza virus replication in cardiomyocytes drives heart dysfunction and fibrosis

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SCIENCE ADVANCES
卷 8, 期 19, 页码 -

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AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.abm5371

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资金

  1. NIH [AI130110, AI151230, AI142256, AI146252, AI148669, AI132962, HL154001, AI146690]
  2. Ohio State University Systems and Integrative Biology Training Program - NIH [GM068412]
  3. Ohio State University Presidential Fellowship
  4. Ohio State University Infectious Diseases Institute - NIH [AI112542]
  5. Ohio State University College of Medicine
  6. National Science Foundation GRFP Fellowship

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Cardiac dysfunction is a common complication of severe influenza virus infection, and it is unclear whether this occurs through direct infection of cardiac tissue or indirectly through systemic lung inflammation. In this study, a novel recombinant heart-attenuated influenza virus was generated, and it was found that robust virus replication in the heart is required for pathology, even when lung inflammation is severe.
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.

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