MUCOSAL INFECTION WITH ARENAVIRUS

ArenaVirus是一种由啮齿动物传播的病毒，当传播给人类时会导致致命疾病。非洲的拉沙热病毒和玻利维亚的马丘波病毒是过去几年中引起注意的两种病毒。淋巴细胞性脉络膜脑膜炎病毒(LCMV)的原型病毒经常被用于研究近交系小鼠的细胞免疫。然而，小鼠感染不适合人类的阿雷诺病毒疾病，因为人类疾病更具毒性，有不同的致病机制。此外，实验性感染主要采用非肠道接种途径，而粘膜接种(通过吸入或摄入)是最常见的自然感染途径。对其他病毒系统的研究，特别是对艾滋病的猴子模型，表明接种途径深刻地影响了感染的发病机制和免疫反应。由于对粘膜接种后的ArenaVirus感染知之甚少，我们建议进行一项初步研究，将我们的小鼠粘膜研究扩展到非人类灵长类动物。在恒河猴胃内接种后，我们将收集有关病毒水平和分布、免疫反应的时间进程和病理进展的信息。我们将使用猴的LCMV感染，这与猴子的拉沙热病毒感染非常相似。我们将检验一种假设，即恒河猴粘膜LCMV感染具有小鼠粘膜LCMV感染的几个特征，但在发病机制上有根本的不同。我们收集的信息将对人类疾病和影响非人类灵长类动物的疾病(例如，新大陆圈养灵长类动物的一种新出现的疾病)具有重要意义。有关免疫反应时间进程的信息将为疫苗诱导的免疫反应提供里程碑。因此，这些信息将作为开发针对黏膜Arena病毒感染的黏膜疫苗和药物治疗的基础。

Arenaviruses are rodent-borne viruses that cause fatal illness when transmitted to man. Lassa fever virus in Africa and Machupo virus in Bolivia are two arenaviruses that have caused noteable outbreaks in the last few years. The prototype arenavirus, lymphocytic choriomeningitis virus (LCMV), has frequently been used to study cell-mediated immunity in inbred mice. However murine infection is an inappropriate model for arenavirus disease in man, because human disease is more virulent and has a different pathogenic mechanism. Furthemore, experimental infections have employed primarily parenteral routes of inoculation, and mucosal inoculation (through inhalation or ingestion) is the most frequent natural route of infection. Studies with other viral systems, particularly the monkey model for AIDS, illustrate that the route of inoculation profoundly influences the pathogenesis and immune responses to infection. Since little is known about arenavirus infection after mucosal inoculation, we propose a pilot study to extend our murine mucosal studies to the nonhuman primate. After intragastric inoculation of rhesus macaques we will collect information about the level and distribution of virus, the timecourse of immune responses, and the progression of pathology. We will employ LCMV infection of monkeys, which strongly resembles Lassa fever virus infection of monkeys. We will test the hypothesis that mucosal LCMV infection of the rhesus macaque shares several features of murine mucosal LCMV infection, but differs fundamentally in pathogenesis. The information we collect will be important for human disease and for diseases affecting nonhuman primates (e.g., callitriched hepatitis, an emerging disease of captive New World primates). The information about immune response timecourse will provide landmarks for vaccine-elicited immune responses. Thus, this information will serve as the basis for developing mucosal vaccines and pharmacological treatments that target mucosal arenavirus infections.