Development of a new model of viral hemorrhagic fever.

描述（由申请人提供）：猕猴感染猴出血热病毒（SHFV）会导致快速发病，致命的出血性疾病。相比之下，非洲猴子物种，如斑猴、非洲绿猴和狒狒，会出现无症状的急性或持续性SHFV感染。高水平的病毒血症已被记录在持续感染的猴身上。用长期持续感染的猴血接种的猕猴迅速发展为出血性疾病。SHFV是一种BSL2水平的病原体，不会感染人类。该项目的最终目标是开发一种BSL2型病毒性出血热动物模型，可用于开发和测试出血性疾病的“通用”对策。由SHFV引起的猕猴出血性疾病与其他BSL4型出血热病毒如埃博拉扎伊尔病毒引起的出血性疾病非常相似。尽管SHFV在两种动物中都能有效复制，但在猕猴和非洲猴之间观察到的疾病结果的巨大差异为解剖引发出血性疾病的病毒和宿主因素提供了一个独特的系统。提出了一个SHFV反向遗传系统的构建和测试。该系统将用于开始研究参与触发宿主细胞反应的病毒蛋白。由于目前对SHFV的细胞反应基本上一无所知，因此提出了在抗病和易感猴子的单核细胞、巨噬细胞和树突状细胞培养物中进行SHFV复制的比较研究。细胞对SHFV的反应将通过多种方法进行检测。将分析促炎细胞因子的产生、组织因子细胞表面表达和基因表达模式。该研究将提供关于触发或阻止SHFV感染出血反应的细胞因子/途径和病毒蛋白的初步见解，并将为该模型的进一步开发提供所需的试剂。该项目的长期目标是开发一种新的病毒性出血热BSL2模型，这将对测试治疗出血性疾病的新型“通用”疗法有价值。进一步开发该模型所需的病毒试剂将被生成，并且对来自疾病抗性和易感猴的细胞对猴出血热病毒的初始反应进行初步比较研究，将为引发病毒性出血病的机制提供进一步的见解。

DESCRIPTION (provided by applicant): Infection of macaque monkeys with simian hemorrhagic fever virus (SHFV) causes a rapid onset, fatal hemorrhagic disease. In contrast, species of African monkeys, such as patas monkeys, African green monkeys and baboons, develop asymptomatic acute or persistent SHFV infections. High levels of viremia have been documented in persistently infected patas monkeys. Macaques inoculated with the blood of long term persistently infected patas monkeys rapidly develop hemorrhagic disease. SHFV is a BSL2 level agent which does not infect humans. The ultimate goal of this project is to develop a BSL2 animal model of viral hemorrhagic fever which can be used for the development and testing of "generic" countermeasures of hemorrhagic disease. The hemorrhagic disease caused by SHFV in macaques is very similar to that caused by other BSL4 hemorrhagic fever viruses such as Ebola Zaire virus. The dramatic difference in disease outcome observed between macaques and African monkeys, even though SHFV replicates efficiently in both types of animals provides a unique system for dissecting the viral and host factors involved in triggering hemorrhagic disease. The construction and testing of a reverse genetic system for SHFV is proposed. This system will be used to begin the study of viral proteins involved in triggering host cell responses. Since essentially nothing is currently known about the cellular response to SHFV, comparative studies of SHFV replication in monocyte, macrophage and dendritic cell cultures from disease resistant and disease susceptible monkeys is proposed. Cell responses to SHFV will be assayed by a variety of methods. Proinflamnmtory cytokine production, tissue factor cell surface expression and gene expression patterns will be analyzed. This study will provide preliminary insights about the cellular factors/pathways and viral proteins that trigger or prevent a hemorrhagic response to SHFV infection and will provide reagents needed for further development of this model. The long term goal of this project is the development of a new BSL2 model of viral hemorrhagic fever that will be valuable for testing novel "generic" therapies for the treatment of hemorrhagic disease. Viral reagents needed for the further development of this model will be generated and preliminary comparative studies of the initial responses to simian hemorrhagic fever virus in cells from disease resistant and susceptible monkeys will provide further insights into the mechanisms involved in triggering viral hemorrhagic disease.