title: Conditional transgenic expression of TIR-domain-containing adaptor-inducing interferon-β (TRIF) in the adult mouse heart is protective in acute viral myocarditis.
abstract: TIR-domain-containing adaptor-inducing interferon-β (TRIF) plays a major role in Toll-like receptor 3 (TLR3) mediated signaling. Mice deficient in TLR3 and TRIF have been shown to be highly susceptible to enterovirus-induced myocardial injury. These mice have decreased production of antiviral cytokines and increased viral replication in the heart. Therefore, we hypothesized that conditional overexpression of TRIF would change cardiac myocyte susceptibility to virus infection by augmenting the antiviral response. We generated double-transgenic MHC-tTA/MHC(tetO)-TRIF mice (DT), with conditional cardiac-specific overexpression of TRIF. Naive DT mice had increased cardiac expression of antiviral cytokines and increased cellular infiltration but no alterations in cardiac function. DT mice were less susceptible to encephalomyocarditis virus (EMCV) infection and had a significantly lower viral load in the heart when compared to littermate (LM) and MHC(tetO)-TRIF (ST) mice. Histopathological examination showed that the severity of myocarditis was also attenuated in DT mice. Furthermore, the decreased virus titers in the DT mouse hearts led to less cardiac damage and better cardiac function when compared to LM and ST mice. Administration of doxycycline to DT mice suppressed the protective effects of TRIF overexpression in the heart. The findings of the present study establish the importance of cardiac-specific TRIF-mediated signaling in the heart in acute viral myocarditis and identify potentially important targets for diagnostic and therapeutic strategies.
authors.affiliation: Department of Pediatrics, Baylor College of Medicine and Texas Children's Hospital, 1102 Bates Street, FC 430.09, Houston, TX 77030, USA.
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Xu
authors.forename: Moreshwar
authors.initials: M
authors.lastname: Desai
authors.forename: Joseph
authors.initials: J
authors.lastname: Philip
authors.forename: Natarajan
authors.initials: N
authors.lastname: Sivsubramanian
authors.forename: Neil E
authors.initials: NE
authors.lastname: Bowles
authors.forename: Jesus G
authors.initials: JG
authors.lastname: Vallejo
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics* / Q000276:immunology; D000818:Animals; D015153:Blotting, Western; D018188:Cardiovirus Infections / Q000235:genetics* / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis; D004452:Echocardiography; D004686:Encephalomyocarditis virus; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006321:Heart; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009205:Myocarditis / Q000235:genetics* / Q000276:immunology / Q000821:virology*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D019562:Viral Load
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D016207:Cytokines; C476286:Ticam1 protein, mouse