Crystal structures and mechanism of disease of the astrovirus capsid protein

描述（由申请人提供）：星状病毒是幼儿病毒性腹泻的主要原因，可导致免疫功能低下儿童的慢性腹泻甚至全身性感染。目前尚无针对星状病毒感染的疫苗和抗病毒疗法。尽管它们具有重要的医学意义，但星状病毒诱发疾病的机制尚不清楚。最近，我的合作者Stacey Schultz-Cherry博士的实验室首次在动物模型中证明了星状病毒衣壳蛋白单独引起腹泻，这表明它是一种新型的病毒性肠毒素（手稿正在准备中）。体外和体内研究表明，衣壳蛋白通过重组肌动蛋白细胞骨架，打开细胞紧密连接，增加肠上皮细胞的通透性，从而诱导腹泻。我们对这种独特的病毒性肠毒素的结构有一个基本的了解缺口。这一信息不仅会导致有针对性的抗病毒方法

DESCRIPTION (provided by applicant): Astroviruses are a leading cause of viral diarrhea in young children and can be associated with chronic diarrhea and even systemic infection in immunocompromised children. Vaccines and antiviral therapies for astrovirus infection are unavailable. In spite of their medical importance, the mechanism of astrovirus-induced disease is unknown. Recently, the laboratory of my collaborator, Dr. Stacey Schultz-Cherry, demonstrated for the first time that the astrovirus capsid protein alone induced diarrhea in an animal model suggesting that it functions as a novel viral enterotoxin (manuscript in preparation). In vitro and in vivo studies showed that the capsid protein induced diarrhea by increasing the permeability of intestinal epithelial cells by reorganizing the actin cytoskeleton and opening the cellular tight junctions. A fundamental gap in our knowledge is the structure of this unique viral enterotoxin. This information will not only lead to targeted antiviral approaches but may aid in the identification of other structurally similar proteins with toxin-like properties The goals of my research are to determine the structures and mechanism of disease of the astrovirus capsid protein. Further, I will identify the toxigenic domain and determine the structural basis for astrovirus antigenicity and species specificity. I will combine my expertise i structural biology and Dr. Schultz-Cherry's expertise with astrovirus biology to take a coordinated and hypothesis-driven approach to investigate the molecular mechanisms of astrovirus entry and pathogenesis by the capsid protein. We are uniquely suited to undertake these studies given our combined expertise in structural biology, biochemistry, cell biology, and virology leading to an interdisciplinary research program that will reveal the mechanism of astrovirus entry and pathogenesis. Furthermore, this work will be the basis for translational research in vaccine design, antiviral drug design, and development of astrovirus as a nanoparticle drug delivery vehicle.