Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, USA.
Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan, USA.
J Virol. 2015 Jan;89(1):468-79. doi: 10.1128/JVI.02077-14. Epub 2014 Oct 15.
Adenoviruses are frequent causes of pediatric myocarditis. Little is known about the pathogenesis of adenovirus myocarditis, and the species specificity of human adenoviruses has limited the development of animal models, which is a significant barrier to strategies for prevention or treatment. We have developed a mouse model of myocarditis following mouse adenovirus 1 (MAV-1) infection to study the pathogenic mechanisms of this important cause of pediatric myocarditis. Following intranasal infection of neonatal C57BL/6 mice, we detected viral replication and induction of interferon gamma (IFN-γ) in the hearts of infected mice. MAV-1 caused myocyte necrosis and induced substantial cellular inflammation that was composed predominantly of CD3(+) T lymphocytes. Depletion of IFN-γ during acute infection reduced cardiac inflammation in MAV-1-infected mice without affecting viral replication. We observed decreased contractility during acute infection of neonatal mice, and persistent viral infection in the heart was associated with cardiac remodeling and hypertrophy in adulthood. IFN-γ is a proinflammatory mediator during adenovirus-induced myocarditis, and persistent adenovirus infection may contribute to ongoing cardiac dysfunction.
Studying the pathogenesis of myocarditis caused by different viruses is essential in order to characterize both virus-specific and generalized factors that contribute to disease. Very little is known about the pathogenesis of adenovirus myocarditis, which is a significant impediment to the development of treatment or prevention strategies. We used MAV-1 to establish a mouse model of human adenovirus myocarditis, providing the means to study host and pathogen factors contributing to adenovirus-induced cardiac disease during acute and persistent infection. The MAV-1 model will enable fundamental studies of viral myocarditis, including IFN-γ modulation as a therapeutic strategy.
腺病毒是小儿心肌炎的常见病因。腺病毒心肌炎的发病机制知之甚少，且人类腺病毒的种属特异性限制了动物模型的发展，这是预防或治疗策略的一个重大障碍。我们通过感染鼠腺病毒 1（MAV-1）建立了心肌炎的小鼠模型，以研究这种小儿心肌炎重要病因的发病机制。通过对新生 C57BL/6 小鼠进行鼻腔内感染，我们检测到感染小鼠心脏中的病毒复制和干扰素 γ（IFN-γ）的诱导。MAV-1 引起心肌细胞坏死，并诱导大量以 CD3(+)T 淋巴细胞为主的细胞炎症。在急性感染期间 IFN-γ耗竭可减少 MAV-1 感染小鼠的心脏炎症，而不影响病毒复制。我们观察到新生小鼠急性感染期间收缩力下降，且持续性病毒感染与成年后心脏重塑和肥大有关。IFN-γ是腺病毒诱导心肌炎中的促炎介质，持续性腺病毒感染可能导致持续的心脏功能障碍。
研究不同病毒引起的心肌炎的发病机制对于描述导致疾病的病毒特异性和非特异性因素至关重要。腺病毒心肌炎的发病机制知之甚少，这是治疗和预防策略发展的重大障碍。我们使用 MAV-1 建立了人类腺病毒心肌炎的小鼠模型，为研究急性和持续性感染中宿主和病原体因素导致腺病毒相关心脏疾病提供了手段。MAV-1 模型将使包括 IFN-γ调节作为治疗策略在内的病毒性心肌炎的基础研究成为可能。
