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)会导致一种快速发病的致命出血性疾病。相比之下，非洲猴子的物种，如帕塔斯猴、非洲绿猴和狒狒，会发展成无症状的急性或持续性SHFV感染。在持续感染的帕塔斯猴中发现了高水平的病毒血症。被长期感染的恒河猴的血液接种的猕猴很快就会患上出血性疾病。SHFV是一种BSL2级病毒，不会感染人类。该项目的最终目标是开发一种BSL2病毒性出血热动物模型，该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出血热病毒如埃博拉扎伊尔病毒引起的非常相似。尽管SHFV在两种动物中有效复制，但在猕猴和非洲猴子之间观察到的疾病结果存在巨大差异，这为剖析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SHFV反向遗传系统的构建和检测方法。该系统将用于开始研究与触发宿主细胞反应有关的病毒蛋白。由于目前对SHFV的细胞反应基本上一无所知，因此对SHFV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中的复制进行了比较研究。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、组织因子细胞表面的表达和基因表达模式。这项研究将提供关于触发或预防SHFV感染的出血性反应的细胞因子/途径和病毒蛋白的初步见解，并将提供进一步发展该模型所需的试剂。该项目的长期目标是开发一种新的BSL2病毒性出血热模型，该模型将对测试治疗出血性疾病的新的“通用”疗法具有价值。将产生进一步开发该模型所需的病毒试剂，对抗病和易感猴子细胞对猴出血热病毒的初步反应进行初步比较研究，将为进一步深入了解引发病毒性出血热疾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.