Cardiac Deletion of the Coxsackievirus-Adenovirus Receptor Abolishes Coxsackievirus B3 Infection and Prevents Myocarditis In Vivo

• Published in: Journal of the American College of Cardiology Vol. 53; no. 14; pp. 1219 - 1226
• Main Authors: Shi, Yu, MD, PhD, Chen, Chen, MSc, Lisewski, Ulrike, MSc, Wrackmeyer, Uta, MSc, Radke, Michael, PhD, Westermann, Dirk, MD, Sauter, Martina, DVM, Tschöpe, Carsten, MD, Poller, Wolfgang, MD, Klingel, Karin, MD, Gotthardt, Michael, MD
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 07.04.2009; Elsevier; Elsevier Limited
• Subjects: Animals; Biological and medical sciences; Cardiology; Cardiology. Vascular system; Cardiomyocytes; Cardiovascular; Cell adhesion & migration; cell adhesion molecules; Coxsackievirus Infections - prevention & control; Dehydrogenases; Deoxyribonucleic acid; DNA; Gene expression; Heart; Hybridization; Internal Medicine; Kinases; Medical sciences; Mice; myocarditis; Myocarditis - prevention & control; Myocarditis - virology; Myocarditis. Cardiomyopathies; Pathogenesis; Proteins; receptors; Receptors, Cytoplasmic and Nuclear - metabolism; Rodents; Signal transduction; Spleen; Stem cells; Transcription Factors - metabolism; viruses; United States > US; California; INF; Coxsackievirus-adenovirus receptor; LV; carboxyfluorescein; TNF; TAMRA; carboxy-tetramethy-lrhodamine; Coxsackievirus B3; lymphocyte protein tyrosine kinase; left ventricle/ventricular; interleukin; WT; noninduced littermate control animals expressing wild-type Coxsackievirus-adenovirus receptor; knockout; cell adhesion molecules; viruses; decay-accelerating factor; IL; receptors; KO; myocarditis; DAF; p.i; interferon; MerCreMer transgenic; FAM; tumor necrosis factor; CAR; LCK; after injection with virus; MCM; CVB3; Heart; Adenoviridae; Picornaviridae; Cardiovascular disease; Enterovirus; Myocardial disease; Virus; Infection; Myocarditis; Prevention; In vivo; Heart disease; Deletion; Circulatory system; Cardiology; Biological receptor
• ISSN: 0735-1097; 1558-3597
• DOI: 10.1016/j.jacc.2008.10.064

Objectives We investigated the role of the Coxsackievirus-adenovirus receptor (CAR) in viral myocarditis. Background CAR is involved in virus uptake into various cell types. It has therefore been suggested as a therapeutic target to prevent or treat Coxsackievirus B3 (CVB3)-induced diseases such as myocarditis and cardiomyopathy. Recent work in CAR-deficient animals has indicated a role in embryonic development and remodeling with cardiac malformation and lethality. Methods We generated a tamoxifen-inducible knockout (KO) mouse to study CAR in the adult heart after CVB3 infection. Histomorphology, virus distribution, and cardiac function were compared in CAR-KO versus noninduced littermate control animals expressing wild-type CAR (WT). Results We have demonstrated that eliminating CAR prevents signs of inflammatory cardiomyopathy, with essentially no pathology in KO hearts. Unlike CVB3-infected WT control animals, the cardiac inducible KO mice did not exhibit structural changes such as monocyte infiltration or fibrosis after CVB3 infection or increased production of markers of inflammation such as interleukin-6 and -10. Whereas CVB3 infection resulted in severe contractile dysfunction in the hearts of animals that express WT, the CAR-deficient hearts appeared normal. Conclusions Elimination of CAR in adult hearts can efficiently block virus entry and the associated pathology including contractile dysfunction. The lack of infiltration or other morphological changes in CVB3-infected KO hearts emphasizes the contribution of direct virus-mediated pathology in enteroviral myocarditis.