Adenovirus myocarditis: defining host factors contributing to pathogenesis

腺病毒心肌炎：确定导致发病机制的宿主因素

• 批准号: 8719804
• 负责人: Jason Brice Weinberg
• 金额: $ 19.43万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-10 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8719804
• 关键词: Acute; Acute Myocarditis; Adenovirus Infections; Adenoviruses; Adult; Age; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antiviral Agents; Cardiac; Cardiac Myocytes; Child; Data; Disease; Equilibrium; Goals; Heart; Human Adenovirus Infections; Human Adenoviruses; Immune; Immune response; In Vitro; Infection; Inflammation; Integration Host Factors; Interferons; Lymphocyte; Mediating; Modeling; Mouse Strains; Mus; Muscle Cells; Myocarditis; Outcome; Pathogenesis; Patients; Predisposition; Process; Production; Proteins; Publishing; Recruitment Activity; Research; Species Specificity; System; Testing; Therapeutic; Vaccines; Viral; Viral Pathogenesis; Virus; Virus Diseases; Work; age related; base; cytokine; effective therapy; human disease; immunoregulation; improved; in vivo; neonate; novel; novel strategies; pathogen; public health relevance; research study; response; therapeutic target

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.

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以及心肌细胞凋亡。干扰素是具有抗病毒活性的关键细胞因子，可提供 在许多病毒性心肌炎模型中具有保护作用。然而，许多病毒已经进化出逃避宿主干扰素反应的机制。心肌炎与人类腺病毒（Ad）感染之间的关联已得到充分证实，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 1 型腺病毒 (MAV-1) 来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在体外感染心肌细胞，在体内感染心脏； 2) MAV-1诱导干扰素产生； 3)淋巴细胞被募集至MAV-1感染动物的心脏。在本提案描述的实验中，我们将在多种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。我们将检验总体假设，即病毒免疫调节和干扰素等保护性宿主因素之间的平衡决定了腺病毒心肌炎的结果。目前尚无有效的疫苗和抗病毒药物来提供针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尚未显示出对病毒性心肌炎患者一致的益处。因此，有必要更好地了解导致疾病的病毒和宿主因素，以便制定有效的预防或治疗策略。 MAV-1为腺病毒发病机制的研究提供了具有独特优势的模型。