Development of a new model of viral hemorrhagic fever.

病毒性出血热新模型的开发。

• 批准号: 7501890
• 负责人: Margo A Brinton
• 金额: $ 17.72万
• 依托单位: GEORGIA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7501890
• 关键词: Acute; African; Animal Model; Animals; Arterivirus; Biological Assay; Blood; Cell surface; Cells; Cercopithecus pygerythrus; Comparative Study; Containment; Data; Dendritic Cells; Development; Disease; Disease Outcome; Disease Resistance; Erythrocebus patas; Facility Construction Funding Category; Gene Expression; Generic Drugs; Genome; Goals; Human; Infection; Integration Host Factors; Macaca; Methods; Modeling; Monkey Hemorrhagic Disease Virus; Monkeys; Papio; Pathway interactions; Pattern; Phase; Production; RNA; Reagent; System; Testing; Thromboplastin; Viral; Viral Hemorrhagic Fevers; Viral Proteins; Viremia; Virus; Virus Diseases; Virus Replication; Work; Zaire Ebola virus; cytokine; hemorrhagic fever virus; insight; macrophage; model development; monocyte; novel; positional cloning; prevent; response; success; virus host interaction

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.

描述（由申请人提供）：猕猴感染猿猴出血热病毒（SHFV）会导致一种快速发病的致命出血性疾病。相比之下，非洲猴类，如帕塔猴、非洲绿猴和狒狒，会出现无症状的急性或持续性 SHFV 感染。在持续感染的帕塔猴中已发现高水平的病毒血症。猕猴接种了长期持续感染的帕塔猴的血液，很快就会患上出血性疾病。 SHFV 是 BSL2 级病毒，不会感染人类。该项目的最终目标是开发病毒性出血热的 BSL2 动物模型，可用于开发和测试出血性疾病的“通用”对策。 SHFV 在猕猴中引起的出血性疾病与其他 BSL4 出血热病毒（例如扎伊尔埃博拉病毒）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独特的系统。提出了 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，因此建议对抗病猴和易感猴的单核细胞、巨噬细胞和树突状细胞培养物中的 SHFV 复制进行比较研究。细胞对 SHFV 的反应将通过多种方法进行测定。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。这项研究将提供有关触发或预防 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病毒性出血热 BSL2 模型，该模型对于测试治疗出血性疾病的新型“通用”疗法非常有价值。将产生进一步开发该模型所需的病毒试剂，并且对抗病和易感猴子的细胞中对猿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性疾病的机制提供进一步的见解。

项目成果

New insights about the regulation of Nidovirus subgenomic mRNA synthesis.

关于 Nidovirus 亚基因组 mRNA 合成调控的新见解。

• 发表时间: 2018
• 影响因子: 3.7
• 作者: Di, Han;McIntyre, Ayisha A;Brinton, Margo A
• 通讯作者: Brinton, Margo A

Functional analyses of the three simian hemorrhagic fever virus nonstructural protein 1 papain-like proteases.

三种猿猴出血热病毒非结构蛋白1木瓜蛋白酶的功能分析。

• 发表时间: 2014-08
• 作者: Vatter, Heather A;Di, Han;Donaldson, Eric F;Radu, Gertrud U;Maines, Taronna R;Brinton, Margo A
• 通讯作者: Brinton, Margo A

Insertion position as well as the inserted TRS and gene sequences differentially affect the retention of foreign gene expression by simian hemorrhagic fever virus (SHFV).

插入位置以及插入的 TRS 和基因序列对猴出血热病毒 (SHFV) 外源基因表达的保留有不同的影响。

• DOI: 10.1016/j.virol.2018.09.014
• 发表时间: 2018-12
• 期刊: Virology
• 影响因子: 3.7
• 作者: Di H;Morantz EK;Sadhwani H;Madden JC Jr;Brinton MA
• 通讯作者: Brinton MA

Each of the eight simian hemorrhagic fever virus minor structural proteins is functionally important.

猿猴出血热病毒的八种次要结构蛋白中的每一种都具有重要的功能。

• DOI: 10.1016/j.virol.2014.06.001
• 发表时间: 2014-08
• 期刊: Virology
• 影响因子: 3.7
• 作者: Vatter, Heather A.;Di, Han;Donaldson, Eric F.;Baric, Ralph S.;Brinton, Margo A.
• 通讯作者: Brinton, Margo A.