IFITM3 protects the heart during influenza virus infection

Abstract

Influenza virus primarily targets the lungs, but dissemination and damage to heart tissue is also known to occur in severe infections. Despite this knowledge, influenza virus-induced cardiac pathogenesis and its underlying mechanisms have been difficult to study due to a lack of small animal models. In humans, polymorphisms in the gene encoding interferoninduced transmembrane protein 3 (IFITM3), an antiviral restriction factor, are associated with susceptibility to severe influenza, but whether IFITM3 deficiencies contribute to other aspects of pathogenesis, including cardiac dysfunction, is unknown. We now show that IFITM3 deficiency in a newly generated knockout (KO) mouse model exacerbates illness and mortality following influenza A virus infection. Enhanced pathogenesis correlated with increased replication of virus in the lungs, spleens, and hearts of KO mice relative to wildtype (WT) mice. IFITM3 KO mice exhibited normal cardiac function at baseline, but developed severely aberrant electrical activity upon infection, including decreased heart rate and irregular, arrhythmic RR (interbeat) intervals. In contrast, WT mice exhibited a mild decrease in heart rate without irregularity of RR intervals. Heightened cardiac virus titers and electrical dysfunction in KO animals was accompanied by increased activation of fibrotic pathways and fibrotic lesions in the heart. Our findings reveal an essential role for IFITM3 in controlling influenza virus replication and pathogenesis in heart tissue and establish IFITM3 KO mice as a powerful model to study virus-induced cardiac dysfunction.3

The IFITM protein family in adaptive immunity

“…In mice, IFITM3 protects against influenza, and Ifitm3 À/À mice die when infected with doses of influenza virus that would not be lethal in wild-type (WT) mice. 49,50 In addition to its protective role in other cell types, such as respiratory epithelial cells and the heart, 49,68 IFITM3 protects cells of the immune system from viral infection, thereby enabling them to mount an effective immune response. 7,8,38 During influenza infection, IFITM3 is upregulated in dendritic cells in the lung by type I IFN, allowing them to survive and migrate to the draining lymph node in order to present viral antigens.…”

Grouper interferon-induced transmembrane protein 3 (IFITM3) inhibits the infectivity of iridovirus and nodavirus by restricting viral entry

“…Similarly, overexpression of chicken or duck IFITM3 could restrict ATMUV infection, as reflected by lower TCID 50 titers and a decrease in viral gene expression, while knockdown of IFITM3 significantly promoted ATMUV replication [21]. Moreover, IFITM3 knockout in a mouse model increased the replication of influenza virus in the lungs, spleen, and heart [52]. In accordance with these previous studies, overexpression of EcIFITM3 significantly reduced CPE severity upon SGIV and RGNNV infection, reduced SGIV production, and inhibited the mRNA and protein expression of viral genes, while knockdown of EcIFITM3 significantly promoted the replication of SGIV and RGNNV, suggesting that EcIFITM3 suppresses viral gene expression, and thereby restricts DNA and RNA virus infection in fish.…”