Pathogenesis of myocarditis

描述（由申请人提供）：我们实验室最近的实验证明柯萨奇b3 （CBS）病毒诱导人细胞产生IL-6和IL-8。CBS小鼠感染与野生型小鼠心脏组织中细胞因子水平升高有关，而与TLR4或CD14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CBS感染细胞所必需的。这种细胞表面蛋白在小鼠胚胎中大约第10天表达，出生后在包括心脏在内的一些器官中表达减少。然而，人类和啮齿动物的病理检查表明，心肌疾病患者的CAR表达增加。TLR4和CD14敲除小鼠的心脏中出现较低水平的病毒，这表明tlr在病毒性心肌炎中起主要作用。我们计划利用我们在TLR和CAR蛋白表征研究方面的专业知识来定义TLR蛋白、细胞因子和CAR蛋白的相互作用。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tlr（特别是TLR2、TLR4和TLR7）在CBS应答中的作用及其在心肌炎发生中的调控作用。

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.