Basic Research in Cardiology

, Volume 106, Issue 6, pp 1159–1171

Conditional transgenic expression of TIR-domain-containing adaptor-inducing interferon-β (TRIF) in the adult mouse heart is protective in acute viral myocarditis

  • Zhaohui Xu
  • Moreshwar Desai
  • Joseph Philip
  • Natarajan Sivsubramanian
  • Neil E. Bowles
  • Jesus G. Vallejo
Original Contribution

DOI: 10.1007/s00395-011-0226-4

Cite this article as:
Xu, Z., Desai, M., Philip, J. et al. Basic Res Cardiol (2011) 106: 1159. doi:10.1007/s00395-011-0226-4

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/MHCtetO-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 MHCtetO-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.

Keywords

InflammationInfectionInnate immunityCytokinesMyocardial function

Abbreviations

ST

Single trangenic MHC-tetO-TRIF mice

DT

Double-transgenic MHC-tTA/MHCtetO-TRIF mice

cTnI

Cardiac troponin I

Supplementary material

395_2011_226_MOESM1_ESM.ppt (76 kb)
Supplementary material 1 (PPT 75 kb)

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Zhaohui Xu
    • 1
    • 2
  • Moreshwar Desai
    • 1
    • 3
  • Joseph Philip
    • 1
    • 3
  • Natarajan Sivsubramanian
    • 4
  • Neil E. Bowles
    • 5
  • Jesus G. Vallejo
    • 1
    • 2
  1. 1.Department of PediatricsBaylor College of Medicine and Texas Children’s HospitalHoustonUSA
  2. 2.Sections of Infectious DiseasesBaylor College of Medicine and Texas Children’s HospitalHoustonTexas
  3. 3.Critical Care MedicineBaylor College of Medicine and Texas Children’s HospitalHoustonUSA
  4. 4.Department of Medicine, Winters Center for Heart Failure ResearchBaylor College of Medicine and Texas Children’s HospitalHoustonUSA
  5. 5.Department of Pediatrics, Division of CardiologyUniversity of Utah School of MedicineSalt Lake CityUSA