Pathogenesis of myocarditis

描述(申请人提供)：最近在我们实验室的实验证明，柯萨奇B3(CBS)病毒诱导人类细胞产生IL-6和IL-8。感染CBS的小鼠与野生型心脏组织中细胞因子水平的升高有关，而与TLR4或CD14基因敲除小鼠无关。与其他肠道病毒一样，CBS已被证明与补体调节蛋白衰变加速因子(DAF)结合。然而，体外数据表明，柯萨奇和腺病毒受体(CAR)的表达是感染CBS细胞所必需的。这种细胞表面蛋白在大约第10天的小鼠胚胎中表达，出生后在包括心脏在内的一些器官中的表达减少。然而，在人类和啮齿动物身上的病理检查表明，在患有心肌疾病的人中，CAR的表达增加。TLR4和CD14基因敲除的小鼠心脏中的病毒水平较低，这表明TLRs在病毒性心肌炎中发挥了重要作用。我们计划利用我们在TLRs和CAR蛋白研究方面的专业知识来确定TLR蛋白、细胞因子和CAR蛋白之间的相互作用。我们将验证心肌炎的起源与以下假设有关：1)CBS感染肠道组织(胰腺炎)，2)CAR蛋白上调，3)心脏病毒增加。同时，我们将明确CD14和几种TLRs(特别是TLR2、TLR4和TLR7)在CBS反应中的作用及其在心肌炎发生发展中的调节作用。

DESCRIPTION (provided by applicant): Recent experiments in our laboratory have demonstrated that Coxsackie B 3 (CBS) virus induces IL-6 and IL-8 production in human cells. Infection of mice with CBS is associated with elevated levels of cytokines in heart tissue of wild type but not TLR4 or CD14 knockout mice. CBS, like other enteroviruses, has been shown to bind to the complement regulatory protein decay accelerating factor (DAF). In vitro data indicate, however, that expression of the Coxsackie and Adenovirus Receptor (CAR) is required for infection of cells with CBS. This cell surface protein is expressed in mouse embryos at approximately day 10, and expression decreases after birth in some organs, including the heart. However, pathologic examinations in humans and rodents indicate increased expression of CAR in subjects with myocardial disease. TLR4 and CD14 knockout mice develop lower levels of virus in their hearts suggesting a major role for TLRs in viral myocarditis. We plan to use our expertise in characterization of the study of TLRs and the CAR protein to define the interaction of TLR proteins, cytokines, and the CAR protein. We will test the hypothesis that the origin of myocarditis relates to: 1) infection of gut tissue (pancreatitis) by CBS, 2) upregulation of the CAR protein, and 3) increased virus in the heart. At the same time we will define the roles of CD14, and several TLRs (especially TLR2, TLR4 and TLR7) in the response to CBS and its regulation in the development of myocarditis.