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PRE-CLINICAL RESEARCH

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

Yu Shi, MD, PhD^_*, Chen Chen, MSc^_*, Ulrike Lisewski, MSc^_*, Uta Wrackmeyer, MSc^_*, Michael Radke, PhD^_*, Dirk Westermann, MD, Martina Sauter, DVM, Carsten Tschöpe, MD, Wolfgang Poller, MD, Karin Klingel, MD and Michael Gotthardt, MD^_*,,_*

^_* Neuromuscular and Cardiovascular Cell Biology, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany
Department of Cardiology, Charité–Campus Benjamin Franklin, Berlin, Germany
Department of Molecular Pathology, University Hospital Tübingen, Tübingen, Germany; and the
Department of Veterinary and Comparative Anatomy, Pharmacology, and Physiology, Washington State University, Pullman, Washington. This study was supported by the DFG SFB TR19. Dr. Shi and Miss Chen contributed equally to this work

Manuscript received July 30, 2008; revised manuscript received September 16, 2008, accepted October 7, 2008.

^_* Reprint requests and correspondence: Dr. Michael Gotthardt, Max-Delbrück-Center for Molecular Medicine Berlin-Buch, Robert-Rössle-Strasse 10, 13125 Berlin, GermanyVCAPP, Washington State University, Wegner Hall, Room 205, Pullman, Washington 99164-6520 (Email: gotthardt{at}vetmed.wsu.edu).

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.

Key Words: cell adhesion molecules • myocarditis • receptors • viruses

Abbreviations and Acronyms   CAR = Coxsackievirus-adenovirus receptor   CVB3 = Coxsackievirus B3   DAF = decay-accelerating factor   FAM = carboxyfluorescein   IL = interleukin   INF = interferon   KO = knockout   LCK = lymphocyte protein tyrosine kinase   LV = left ventricle/ventricular   MCM = MerCreMer transgenic   p.i. = after injection with virus   TAMRA = carboxy-tetramethy-lrhodamine   TNF = tumor necrosis factor   WT = noninduced littermate control animals expressing wild-type Coxsackievirus-adenovirus receptor

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