MYOCARDITIS--RECEPTORS FOR A CARDIOTROPIC VIRUS

心肌炎——心肌病毒的受体

• 批准号: 6184372
• 负责人: JEFFREY M. BERGELSON
• 金额: $ 20.34万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-05-01 至 2002-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6184372
• 关键词: Adenoviridae; Coxsackievirus; X ray crystallography; cryoelectron microscopy; decay accelerating factor; gene targeting; genetically modified animals; human tissue; immunocytochemistry; in situ hybridization; laboratory mouse; myocarditis; protein structure function; receptor binding; receptor expression; site directed mutagenesis; virus infection mechanism; virus receptors

Viral myocarditis is believed to initiate the pathologic processes that lead to nearly 9,000 deaths from dilated cardiomyopathy in the US each year. Attachment to a receptor molecule expressed on a target cell is a critical first step in the virus life cycle, and expression of specific receptors is and important determinant of virus tropism for particular tissues. Coxsackie B viruses are the major agents of viral myocarditis. We have identified two receptors for these viruses. In earlier work, we showed that decay accelerating factor (DAF), serves as an attachment receptor for a subset of viral strains. We have now purified and cloned another- --novel---cell surface protein, CAR, that functions both in attachment and infection by all six coxsackie B serotypes. Although this proposal is concerned with coxsackieviruses, it is of interest that CAR also functions as the receptor for adenoviruses, another virus group implicated in myocarditis. In the work proposed here, we will define the structural features that are important for coxsackievirus interactions with DAF and CAR, using cryoelectronmicroscopy, site-directed mutagenesis, and x-ray crystallographic techniques. We will also examine the early events in infection that follow attachment to each of the receptors. In addition, we will study the distribution of receptors in human tissues, including cardiac myocytes, to define the relationship between virus tropism and receptor expression. Based on Northern blot analysis, it appears that CAR mRNA is preferentially expressed in the primary target organs for coxsackie infection. Because a murine CAR homologue functions as the coxsackievirus receptor in mice, we will also use murine models, including transgenic and knock-out animals, to define the role of the coxsackie receptor in viral pathogenesis.

病毒性心肌炎被认为是引发心肌炎的病理过程