MUCOSAL INFECTION WITH ARENAVIRUS

沙粒病毒是啮齿动物传播的病毒，传播给人类后会导致致命疾病。非洲的拉沙热病毒和玻利维亚的马丘波病毒是过去几年引起显著疫情的两种沙粒病毒。沙粒病毒的原型，淋巴细胞性脉络丛脑膜炎病毒（LCMV），经常被用来研究细胞介导的免疫在近交小鼠。然而，小鼠感染是人类沙粒病毒病的一个不合适的模型，因为人类疾病毒性更强，具有不同的致病机制。此外，实验性感染主要采用肠外接种途径，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，特别是对猴子艾滋病模型的研究表明，接种途径深刻地影响了感染的发病机制和免疫反应。由于对粘膜接种后沙粒病毒感染知之甚少，我们提出了一项初步研究，将我们的小鼠粘膜研究扩展到非人灵长类动物。在恒河猴胃内接种后，我们将收集有关病毒水平和分布、免疫反应时间和病理进展的信息。我们将采用猴的LCMV感染，这与猴的拉沙热病毒感染非常相似。我们将验证恒河猴粘膜LCMV感染与小鼠粘膜LCMV感染具有几个特征，但在发病机制上有根本不同的假设。我们收集的信息对于人类疾病和影响非人类灵长类动物的疾病（例如，富含营养的肝炎，一种圈养的新大陆灵长类动物的新疾病）将是重要的。有关免疫反应过程的信息将为疫苗引发的免疫反应提供里程碑。因此，这些信息将作为开发针对粘膜沙粒病毒感染的粘膜疫苗和药理学治疗的基础。

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.