Adenovirus myocarditis: defining host factors contributing to pathogenesis

描述（由申请人提供）：急性心肌炎是儿童和成人疾病的重要原因。病毒性心肌炎的发病机制涉及许多相互关联的过程，包括心肌细胞的直接破坏、感染引发的免疫介导的损伤和心肌细胞凋亡。干扰素是具有抗病毒活性的关键细胞因子， 在许多病毒性心肌炎模型中的保护作用。然而，许多病毒已经进化出逃避宿主干扰素应答的机制。心肌炎和人类腺病毒（Ad）感染之间的联系已经得到很好的建立，但严格的物种特异性限制了人类腺病毒发病机制的研究。我们使用小鼠腺病毒1型（MAV-1）研究腺病毒在其自然宿主中的发病机制。我们的初步数据表明，1）MAV-1感染心肌细胞在体外和心脏在体内; 2）MAV-1诱导干扰素的生产;和3）淋巴细胞募集到MAV-1感染的动物的心脏。在本提案中描述的实验中，我们将在多个小鼠品系的新生儿和成年小鼠中使用MAV-1来建立腺病毒心肌炎模型。我们将检验病毒免疫调节和保护性宿主因子（如干扰素）之间的平衡决定腺病毒心肌炎结局的总体假设。目前还没有有效的疫苗和抗病毒药物来提供对腺病毒或其他通常引起病毒性心肌炎的病毒的保护。抗炎和免疫调节策略对病毒性心肌炎患者的益处并不一致。因此，必须更好地了解导致疾病的病毒和宿主因素，以制定有效的预防或治疗策略。MAV-1为腺病毒致病机制的研究提供了一个具有独特优势的模型。

DESCRIPTION (provided by applicant): Acute myocarditis is a significant cause of disease in children and adults. The pathogenesis of viral myocarditis involves many interrelated processes, including direct destruction of cardiac myocytes, immune- mediated damage triggered by infection, and myocyte apotosis. Interferons are key cytokines with antiviral activity that provide protection in many models of viral myocarditis. However, many viruses have evolved mechanisms to evade host interferon responses. Associations between myocarditis and infection with human adenoviruses (Ad) have been well established, but strict species specificity limits studies of human adenovirus pathogenesis. We use mouse adenovirus type 1 (MAV-1) to study the pathogenesis of an adenovirus in its natural host. Our preliminary data suggest that 1) MAV-1 infects cardiac myocytes in vitro and hearts in vivo; 2) MAV-1 induces interferon production; and 3) lymphocytes are recruited to the hearts of MAV-1-infected animals. In the experiments described in this proposal, we will use MAV-1 in neonates and adults of multiple mouse strains to establish a model of adenovirus myocarditis. We will test the overall hypothesis that a balance between viral immunomodulation and protective host factors such as the interferons determines the outcome of adenovirus myocarditis. Effective vaccines and antiviral drugs are not currently available to provide protection against adenoviruses or other viruses that typically cause viral myocarditis. Anti- inflammatory and immunomodulatory strategies have not shown consistent benefits for patients with viral myocarditis. It is therefore essential to gain a better understanding of both viral and host factors that contribute to disease in order to develop effective preventative or therapeutic strategies. MAV-1 provides a model with unique advantages for the study of adenovirus pathogenesis.