DEVELOPMENTAL EXPRESSION OF COXSACKIE ADENOVIRUS RECEPTOR

点击翻译按钮获取中文摘要

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Introduction: We performed a pilot study to establish a non-human primate model of enteroviral infection and myocarditis. Methods: Juvenile cynomolgus monkeys were inoculated via oral (n=1) or intravenous (n=8) routes with a cloned Coxsackievirus B3 (CVB-3) or a CVB-3 /Enterovirus 86 strain (CVB-MCH) isolated from a clinical specimen from a patient with fatal myocarditis. Clinical and echocardiographic assessment was performed at baseline and at days 3, 7, 14, and 28. CVB-3 neutralizing antibody titers were measured. Viral RNA was detected by RT-PCR and culture of plasma and cardiac tissue. Animals were sacrificed at 14 or 28 days and myocardium examined for viral pathology. Results: Infection was achieved by both routes with both CVB-3 strains. Viremia was detected in 6/9, resolving after day 3. All (9/9) generated neutralizing antibody. Two animals infected with 107 infectious units (IU) of CVB-3 became moribund and were sacrificed at day 11 and day 14. Subsequent animals received 106 IU of CVB-3 and appeared well until sacrificed at day 14 (n=3) or day 28 (n=1). Three infected with 106 IU CVB-MCH also appeared well until sacrificed at day 28. Normal ejection fraction was maintained, but four animals had minor wall motion abnormalities. Serum troponin remained normal. Virus was present in myocardium in 5/5 tested. Multiple areas of focal cardiac injury were present in all animals and included lymphocytic or eosinophilic myocarditis (n=6), focal inflammation (n= 3), myocytolysis (n=2), ischemic foci (n=4), contraction band necrosis (n=2), and hypertrophy (n=3). Active myocarditis was present in 4/5 animals at day 14 and 2/4 at day 28. Conclusions: We were able to consistently establish infection with CVB-3 in cynomolgus monkeys resulting in clinically apparent or sub clinical disease, including myocarditis or cardiac injury persisting at 28 days. Despite adequate immune responses to clear viremia, virus persisted in the myocardium. The presence of myocyte hypertrophy and injury at 28 days in this model may provide a basis for experiments aimed at modulating immune or virus induced cardiomyopathy.