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Characterization of arenaviral hemorrhagic fever in a primate model.

机译：灵长类动物模型中沙雷亚病毒性出血热的特征。

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摘要

The Arenaviridae are enveloped negative-stranded RNA viruses that often elicit cell-mediated immunity in mice and can be biothreat agents in primates. Five years ago our laboratory began infections of rhesus macaques with the prototype arenavirus, lymphocytic choriomeningitis virus (LCMV) using the WE strain that has been known to cause both encephalopathy and multifocal hemorrhage. Our initial study established that intravenously-inoculated monkeys developed signs of fatal hemorrhagic fever, whereas monkeys inoculated by the intragastric route had subclinical infections and no gross or microscopic lesions.; In a second study, a high dose of LCMV-WE was delivered intragastrically or intravenously to rhesus macaques. This study contradicted the generally held notion that hemorrhagic fever was characterized by a burst of pro-inflammatory cytokines because we showed that pro-inflammatory cytokines TNF-alpha and IL-1beta were not detected in plasma of infected animals, and that increased gamma interferon could only be detected late in the plasma of fatally infected animals. We proposed that certain pro-inflammatory cytokines like IL-6 were instigators in liver repair, and that disease was due to virus inhibition of repair mechanisms. We observed increases in IL-6, sIL-6R, sTNFR, and proliferation antigen in liver that are similar to the profile of incipient liver regeneration. Although IL-6 was not directly induced by virus infection in vitro, peripheral blood mononuclear cells from acutely infected monkeys produced higher levels of IL-6 than did healthy controls. Our data confirmed that acute infection is associated with weak inflammatory responses in tissues and initiates a program of liver regeneration in primates.; In a final study we characterized infection after mucosal inoculation and further lethal challenge. I used plaque neutralization, ELISA, lymphocyte proliferation, real time RT-PCR, flow-cytometry and chromium-release assays to monitor protective immune responses, and cross-protection between virulent (LCMV-WE) and avirulent (LCMV-ARM) strains. Three out of seven monkeys that experienced protection were also the three with the strongest cell-mediated immunity. Overall, the studies presented in this thesis validate the importance of the mucosally-infected macaque as a valuable model for the pathogenesis of hemorrhagic fever, for characterizing immune responses, and for testing vaccine candidates for Lassa Fever virus.
机译：沙眼病毒是包膜的负链RNA病毒，通常在小鼠中引起细胞介导的免疫，并且可以是灵长类动物的生物威胁因子。五年前，我们的实验室开始使用WE株感染原型恒河猴病毒，淋巴细胞性脉络膜脑膜炎病毒（LCMV）感染恒河猴，这种WE株会引起脑病和多灶性出血。我们的初步研究确定了静脉接种的猴子会出现致命性出血热的迹象，而通过胃内途径接种的猴子具有亚临床感染，没有肉眼或镜下的病变。在第二项研究中，将高剂量的LCMV-WE胃内或静脉内输送至恒河猴。这项研究与普遍认为出血热的特征在于促炎性细胞因子爆发的观点相矛盾，因为我们表明在感染动物的血浆中未检测到促炎性细胞因子TNF-alpha和IL-1beta，而γ干扰素可能会增加。仅在致命感染动物的血浆中被发现较晚。我们提出某些促炎性细胞因子（如IL-6）是肝脏修复的诱因，而该疾病是由于病毒抑制修复机制引起的。我们观察到肝脏中IL-6，sIL-6R，sTNFR和增殖抗原的增加与早期肝再生的特征相似。尽管体外病毒感染并未直接诱导IL-6，但急性感染的猴子的外周血单核细胞产生的IL-6水平要高于健康对照组。我们的数据证实，急性感染与组织中较弱的炎症反应有关，并引发了灵长类动物肝脏再生的程序。在最后的研究中，我们表征了粘膜接种和进一步致死性攻击后的感染。我使用噬菌斑中和，ELISA，淋巴细胞增殖，实时RT-PCR，流式细胞仪和铬释放测定法来监测保护性免疫应答，以及强毒（LCMV-WE）和无毒（LCMV-ARM）菌株之间的交叉保护。在受到保护的七只猴子中，有三只也是细胞介导的免疫力最强的三只。总体而言，本文提出的研究证实了粘膜感染的猕猴作为出血热发病机理，表征免疫应答以及测试拉沙热病毒候选疫苗的重要模型的重要性。

著录项

  • 作者

    Rodas, Juan David.;

  • 作者单位

    The University of Wisconsin - Madison.;

  • 授予单位 The University of Wisconsin - Madison.;
  • 学科 Biology Veterinary Science.; Biology Microbiology.; Health Sciences Pathology.
  • 学位 Ph.D.
  • 年度 2003
  • 页码 280 p.
  • 总页数 280
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 动物学;微生物学;病理学;
  • 关键词

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