A role for toll-like receptor 3 variants in host susceptibility to enteroviral myocarditis and dilated cardiomyopathy
Journal
Journal of Biological Chemistry
Journal Volume
285
Journal Issue
30
Pages
23208-23223
Date Issued
2010
Author(s)
Gorbea C.
Makar K.A.
Pauschinger M.
Pratt G.
Bersola J.L.F.
Varela J.
David R.M.
Banks L.
Li H.
Schultheiss H.-P.
Towbin J.A.
Vallejo J.G.
Bowles N.E.
Abstract
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.
SDGs
Type
journal article