A Role for Toll-like Receptor 3 Variants in Host Susceptibility to Enteroviral Myocarditis and Dilated Cardiomyopathy

• Published in: The Journal of biological chemistry Vol. 285; no. 30; pp. 23208 - 23223
• Main Authors: Gorbea, Carlos, Makar, Kimberly A., Pauschinger, Matthias, Pratt, Gregory, Bersola, Jeathrina L.F., Varela, Jacquelin, David, Ryan M., Banks, Lori, Huang, Chien-Hua, Li, Hua, Schultheiss, Heinz-Peter, Towbin, Jeffrey A., Vallejo, Jesús G., Bowles, Neil E.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 23.07.2010; American Society for Biochemistry and Molecular Biology
• Subjects: 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 B3; Coxsackievirus Infections - genetics; Coxsackievirus Infections - metabolism; Coxsackievirus Infections - pathology; Diseases; DNA Mutational Analysis; Endosomes - metabolism; Enterovirus; Enterovirus - physiology; Female; Genetics/Human; Humans; Immunology; Immunology/Innate Immunity; Immunology/Toll Receptors; Interferons - metabolism; Male; Middle Aged; Molecular Bases of Disease; Molecular Sequence Data; Mutation; Myocarditis - genetics; Myocarditis - metabolism; Myocarditis - pathology; Myocarditis - virology; Phenotype; Protein Transport; Receptors/Toll-like; Toll-Like Receptor 3 - chemistry; Toll-Like Receptor 3 - genetics; Toll-Like Receptor 3 - metabolism; Virus Replication; Viruses/Positive-strand RNA; Viruses/Positive-strand RNA; Receptors/Toll-like; Immunology/Toll Receptors; Immunology/Innate Immunity; Genetics/Human; Diseases
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M109.047464

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 3β (MAP1LC3β). However, TLR3-mediated signaling was restored upon exogenous expression of Beclin 1 or a variant MAP1LC3β 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.