Crimean congo hemorrhagic fever virus glycoproteins

克里米亚刚果出血热病毒糖蛋白

• 批准号: 7028300
• 负责人: Robert W. Doms
• 金额: $ 30.44万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-08 至 2008-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7028300
• 关键词: Africa; Asia; Crimean Congo hemorrhagic fever virus; Middle East; antigen antibody reaction; arthropod borne communicable disease; biotechnology; bioterrorism /chemical warfare; cell fusion; expression cloning; genetic strain; glycoproteins; hemorrhagic fever; immunologic substance development /preparation; monoclonal antibody; neutralizing antibody; virulence; virus RNA; virus antigen; virus infection mechanism; virus protein; virus receptors

DESCRIPTION (provided by applicant): Crimean-Congo Hemorrhagic Fever virus (CCHFV), a member of the genus Nairovirus of the family Bunyaviridae, causes severe disease in humans with high rates of mortality (50%). Humans can become infected through bites of the Ixodid tick, by contact with a CCHFV infected patient during the acute phase of infection, or by contact with blood or tissue from viremic livestock. Based on the high mortality rate of CCHFV and the potential for CCHFV dissemination by aerosolization, CCHFV is considered to be of potential bioterrorism importance and is classified as a Category B agent. Because of the requirement to work with CCHFV under BSL4 conditions, virtually nothing is known about its cell biology, the mechanisms by which it enters cells, the antigenic structure of its glycoproteins or the mechanisms by which antibodies can neutralize the virus. The RNA genome of CCHFV consists of three negative sense segments: the small (S), medium (M) and large (L) genomic RNA segments. The CCHFV RNA M segment encodes the virus glycoproteins, G1 and G2. The G1 protein is unusual in that it has an N-terminal mucin-like domain that is cleaved from the protein post-translationally, a second N-terminal domain that is also cleaved from the protein, and we have recently found that a C-terminal cleavage event occurs as well, resulting in release of much of the cytoplasmic domain of the protein. Over the past year, we have initiated a collaborative study of CCHFV with Dr. Connie Schmaljohn (USAMRIID) and Dr. Adolfo Garcia-Sastre (Mr. Sinai). Our long-term plan is to prepare a Program Project grant to support our work. The intent of this R21 application is to seek support for studies in the Doms lab that will provide the preliminary results needed for the P01 application. In this R21 application, we propose the following three Specific Aims: Aim 1. Clone and analyze CCHFV M protein segments from geographically diverse CCHFV isolates, and develop the expression systems and tools needed to study and compare the G1 and G2 proteins. Aim 2. Characterize a novel panel of monoclonal antibodies directed against the CCHFV G1 and G2 proteins, including a number of neutralizing antibodies. Aim 3. Develop virus pseudotype systems or cell-cell fusion assays that can be used to study CCHFV tropism, fusion and entry mechanisms under BSL2 or BSL3 conditions.

描述（由申请人提供）： Crimean-Congo出血性发烧病毒（CCHFV）是Bunyaviridae家族奈罗内病毒属的成员，导致死亡率高的人类（50％）引起严重疾病。人类可以通过ixodid tick的叮咬，在感染急性阶段与感染的患者接触，或通过与病毒性牲畜的血液或组织接触而被感染。基于CCHFV的高死亡率和通过雾化的CCHFV传播潜力，CCHFV被认为具有潜在的生物恐怖意义，并被归类为B类代理。由于需要在BSL4条件下与CCHFV一起使用，因此几乎对其细胞生物学，进入细胞的机制，其糖蛋白的抗原结构或抗体可以中和该病毒的机制一无所知。 CCHFV的RNA基因组由三个负性段组成：小（S），中（M）和大（L）基因组RNA段。 CCHFV RNA M节编码病毒糖蛋白G1和G2。 G1蛋白是不寻常的，因为它具有N末端粘蛋白样结构域，该结构域与蛋白质后的蛋白质裂解，后者是第二个N末端结构域，它也与蛋白质裂解，并且最近我们发现C-末端断裂发生了蛋白质，导致了许多细胞蛋白蛋白蛋白的蛋白质蛋白蛋白。在过去的一年中，我们与Connie Schmaljohn博士（Usamriid）和Adolfo Garcia-Sastre（Sinai先生）进行了CCHFV的合作研究。我们的长期计划是为支持我们的工作准备计划项目赠款。该R21应用程序的目的是寻求DOMS实验室中的研究支持，该研究将为P01应用程序提供初步结果。在此R21应用中，我们提出以下三个特定目的：目标1。克隆和分析来自地理上不同CCHFV分离株的CCHFV M蛋白段，并开发研究和比较G1和G2蛋白所需的表达系统和工具。 AIM 2。表征针对CCHFV G1和G2蛋白的新型单克隆抗体，包括许多中和抗体。 AIM 3。开发可用于研究BSL2或BSL3条件下的CCHFV热门，融合和进入机制的病毒假型系统或细胞融合测定。