Development of a new model of viral hemorrhagic fever.

描述（由申请方提供）：猕猴感染猿猴出血热病毒（SHFV）可导致快速发作的致死性出血性疾病。相比之下，非洲猴的物种，如非洲猴，非洲绿色猴和狒狒，发展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帕塔猴子。用长期持续感染的猕猴的血液接种的猕猴迅速发展为出血性疾病。SHFV是一种BSL 2水平的病原体，不感染人类。该项目的最终目标是开发一种BSL 2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在猕猴中引起的出血性疾病与由其他BSL 4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。在猕猴和非洲猴之间观察到的疾病结果的显著差异，即使SHFV在两种类型的动物中有效地复制，也提供了一个独特的系统，用于解剖参与触发出血性疾病的病毒和宿主因素。建立了SHFV反向遗传系统并进行了检测。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。由于基本上没有什么是目前已知的细胞反应SHFV，比较研究的SHFV复制单核细胞，巨噬细胞和树突状细胞培养物的疾病抗性和疾病易感的猴子。将通过多种方法测定细胞对SHFV的应答。将分析促炎细胞因子产生、组织因子细胞表面表达和基因表达模式。这项研究将提供有关细胞因子/途径和病毒蛋白的初步见解，触发或防止出血性反应SHFV感染，并将提供进一步开发该模型所需的试剂。该项目的长期目标是开发一种新的BSL 2病毒性出血热模型，这将对测试治疗出血性疾病的新型“通用”疗法有价值。将产生进一步开发该模型所需的病毒试剂，并对来自疾病抗性和易感猴的细胞中对猿猴出血热病毒的初始反应进行初步比较研究，这将进一步深入了解触发病毒性出血性疾病的机制。

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.