A role for Toll-like receptor 3 variants in host susceptibility to enteroviral myocarditis and dilated cardiomyopathy

J Biol Chem. 2010 Jul 23;285(30):23208-23. doi: 10.1074/jbc.M109.047464. Epub 2010 May 14.


The innate antiviral response is mediated, at least in part, by Toll-like receptors (TLRs). TLR3 signaling is activated in response to viral infection, and the absence of TLR3 in mice significantly increases mortality after infection with enteroviruses that cause myocarditis and/or dilated cardiomyopathy. We screened TLR3 in patients diagnosed with enteroviral myocarditis/cardiomyopathy and identified a rare variant in one patient as well as a significantly increased occurrence of a common polymorphism compared with controls. Expression of either variant resulted in significantly reduced TLR3-mediated signaling after stimulation with synthetic double-stranded RNA. Furthermore, Coxsackievirus B3 infection of cell lines expressing mutated TLR3 abrogated activation of the type I interferon pathway, leading to increased viral replication. TLR3-mediated type I interferon signaling required cellular autophagy and was suppressed by 3-methyladenine and bafilomycin A1, by inhibitors of lysosomal proteolysis, and by reduced expression of Beclin 1, Atg5, or microtubule-associated protein 1 light chain 3beta (MAP1LC3beta). However, TLR3-mediated signaling was restored upon exogenous expression of Beclin 1 or a variant MAP1LC3beta fusion protein refractory to RNA interference. These data suggest that individuals harboring these variants may have a blunted innate immune response to enteroviral infection, leading to reduced viral clearance and an increased risk of cardiac pathology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Amino Acid Sequence
  • Animals
  • Autophagy / drug effects
  • Autophagy / genetics
  • Base Sequence
  • Cardiomyopathy, Dilated / genetics*
  • Cardiomyopathy, Dilated / metabolism
  • Cardiomyopathy, Dilated / pathology
  • Cardiomyopathy, Dilated / virology*
  • Cell Line
  • Chloroquine / pharmacology
  • Coxsackievirus Infections / genetics
  • Coxsackievirus Infections / metabolism
  • Coxsackievirus Infections / pathology
  • DNA Mutational Analysis
  • Endosomes / metabolism
  • Enterovirus / physiology*
  • Female
  • Humans
  • Interferons / metabolism
  • Male
  • Middle Aged
  • Molecular Sequence Data
  • Mutation*
  • Myocarditis / genetics*
  • Myocarditis / metabolism
  • Myocarditis / pathology
  • Myocarditis / virology*
  • Phenotype
  • Protein Transport
  • Toll-Like Receptor 3 / chemistry
  • Toll-Like Receptor 3 / genetics*
  • Toll-Like Receptor 3 / metabolism
  • Virus Replication


  • Toll-Like Receptor 3
  • Chloroquine
  • Interferons