A role for Toll-like receptor 3 variants in host susceptibility to enteroviral myocarditis and dilated cardiomyopathy.
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.
Gorbea
Carlos
C
Department of Pediatrics (Division of Cardiology), University of Utah School of Medicine, Salt Lake City, Utah 84112, USA.
Makar
Kimberly A
KA
Pauschinger
Matthias
M
Pratt
Gregory
G
Bersola
Jeathrina L F
JL
Varela
Jacquelin
J
David
Ryan M
RM
Banks
Lori
L
Huang
Chien-Hua
CH
Li
Hua
H
Schultheiss
Heinz-Peter
HP
Towbin
Jeffrey A
JA
Vallejo
Jesús G
JG
Bowles
Neil E
NE
D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000235:genetics; D001483:Base Sequence; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D002460:Cell Line; D002738:Chloroquine / Q000494:pharmacology; D003384:Coxsackievirus Infections / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004252:DNA Mutational Analysis; D011992:Endosomes / Q000378:metabolism; D004770:Enterovirus / Q000502:physiology*; D005260:Female; D006801:Humans; D007372:Interferons / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D009205:Myocarditis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D010641:Phenotype; D021381:Protein Transport; D051196:Toll-Like Receptor 3 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D014779:Virus Replication
D051196:Toll-Like Receptor 3; D002738:Chloroquine; D007372:Interferons
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