Gauntt C, Higdon A, Bowers D, Maull E, Wood J, Crawley R
Department of Microbiology, University of Texas Health Science Center, San Antonio 78284-7758.
Scand J Infect Dis Suppl. 1993;88:49-65.
Several well-defined coxsackievirus B3 (CVB3)-murine models of inflammatory heart disease are providing information about mechanisms which contribute to myocyte necrosis. Severity of disease induced and mechanisms responsible depend upon unresolved molecular activities of the viral genome, nonspecific defenses of the mouse at time of infection and immune responses of the mouse at the time of infection. Most important are the capabilities and directed responses of each mouse to infection which are determined by age and genetic background of the host. In addition to virus-induced contributions to tissue pathology during primary infection, persistence of viral genomes for week to months in some strains of mice forecast whether the acute disease will resolve or continue as chronic disease with sustained inflammatory reactions in the myocardium. Persistent infections can contribute to nascent cardiopathologic alterations by chronic induction of inflammatory events through expression of viral genes and altered expression of host genes during nonlytic infections. Products of these expressions include viral proteins and nonhomeostatic levels of cytokines and arachidonic acid cascade intermediates and final metabolites. Molecular mimicry via shared epitopes between virion capsid proteins and normal cell molecules/structures located on or within heart tissue cells may be the mechanism by which immune systems in certain strains of mice are persistently stimulated. The products of these immune responses, i.e. antibodies and cytotoxic T lymphocytes, may provide initial protection via termination of infection and virus clearance during acute disease but subsequently these autoreactive processes could contribute to chronic disease. The immune effector products (antibodies and T lymphocytes) have potential pro-inflammatory reactivities, capacity for exacerbating ongoing CVB3-induced disease and/or can induce disease in normal animals. In further support of the hypothesis that autoimmune reactions contribute to sustained inflammation of the heart, non-viral models of myocarditis have been developed. Cell constituents such as myosin and adenosine nucleotide translocator protein can induce cardiopathologic alterations in normal mice of strains known to develop CVB3-induced chronic disease. Thus host genetic background determines whether a mouse survives the initial infection, resolves the acute disease or inadvertently contributes to sustained inflammatory heart disease. Finally, shared epitopes among the enteroviruses may play a role in repeated episodes of disease during sequential infections by different serotypes.
几种明确的柯萨奇病毒B3（CVB3）诱导的小鼠炎症性心脏病模型，正在为导致心肌细胞坏死的机制提供相关信息。所诱导疾病的严重程度及相关机制，取决于病毒基因组未解决的分子活性、小鼠在感染时的非特异性防御以及小鼠在感染时的免疫反应。其中最重要的是每只小鼠对感染的能力和定向反应，这由宿主的年龄和遗传背景决定。除了在初次感染期间病毒对组织病理学的影响外，病毒基因组在某些品系小鼠中持续存在数周甚至数月，预示着急性疾病是否会消退，还是会持续发展为伴有心肌持续炎症反应的慢性疾病。持续性感染可通过在非裂解感染期间表达病毒基因以及改变宿主基因表达，慢性诱导炎症事件，从而导致新生的心脏病理改变。这些表达产物包括病毒蛋白、细胞因子和花生四烯酸级联中间体及最终代谢产物的非稳态水平。病毒衣壳蛋白与心脏组织细胞上或细胞内的正常细胞分子/结构之间通过共享表位进行分子模拟，可能是某些品系小鼠免疫系统受到持续刺激的机制。这些免疫反应的产物，即抗体和细胞毒性T淋巴细胞，可能在急性疾病期间通过终止感染和清除病毒提供初始保护，但随后这些自身反应性过程可能导致慢性疾病。免疫效应产物（抗体和T淋巴细胞）具有潜在的促炎反应性，能够加剧正在进行的CVB3诱导的疾病，和/或在正常动物中诱发疾病。为进一步支持自身免疫反应导致心脏持续炎症这一假说，人们开发了非病毒性心肌炎模型。诸如肌球蛋白和腺苷酸转位蛋白等细胞成分，可在已知会发生CVB3诱导的慢性疾病的品系正常小鼠中诱发心脏病理改变。因此，宿主遗传背景决定了小鼠是否能在初次感染中存活、急性疾病是否会消退，或者是否会无意中导致持续性炎症性心脏病。最后，肠道病毒之间的共享表位可能在不同血清型的连续感染期间的疾病复发中起作用。
