Lack of protective immunity to murine norovirus infection

杯状病毒科中的人类诺如病毒是非细菌性流行性胃肠炎的主要原因 全世界。原发人类诺沃克病毒感染不会引起持久的保护性免疫，这一事实可能 极大地影响疫苗接种策略的效果。我们的长期目标是通过以下方式阐明这些机制 哪些诺如病毒避免了保护性免疫的诱导，最终将这种知识转化为 成功的疫苗接种方法。关于人类诺如病毒的发病机制知之甚少 或控制它们的免疫反应，因为以前没有小动物模型或细胞 感染的培养体系。我们实验室的数据已经确定了第一个诺沃克病毒的小动物模型 感染：我们发现了第一个小鼠诺如病毒(MNV)，MNV-1，并证明了它的培养 巨噬细胞和树突状细胞体外培养。我们现在已经使用这些独特的模型来检测诺沃克病毒 发病机制和免疫。我们已经确定MNV-1是经口感染并引起胃肠炎的， 证实了该病毒作为研究人诺如病毒致病机制的模型的实用性。重要的是，我们有 也确定了MNV-1的原发感染不能提供与同源病毒重新攻击的保护。 因此，MNV-1代表了一个有价值的模型，用来剖析缺乏MNV-1的病理生理学基础。 对人类诺沃克病毒感染的持久保护。我们的具体假设是诺沃克病毒感染未能 诱导保护性黏膜免疫，因为病毒感染粘膜树突状细胞并防止 它们的完全激活。具体地说，我们将确定MNV-1感染是否直接或间接抑制 树突状细胞激活以及MNV-1感染是否刺激调节性T细胞。我们的最终目标是 了解这些对粘膜树突状细胞的影响如何阻止保护性诺如病毒的刺激 并将这一信息转化为有效的疫苗设计。

Human noroviruses in the Caliciviridae family are the major cause of non-bacterial epidemic gastroenteritis worldwide. Primary human norovirus infection does not elicit lasting protective immunity, a fact that could greatly affect the efficacy of vaccination strategies. Our long term goal is to elucidate the mechanisms by which noroviruses avoid the induction of protective immunity, ultimately translating this knowledge into successful vaccination approaches. Little is known regarding the pathogenesis of human noroviruses or the immune responses that control them because there has previously been no small animal model or cell culture system of infection. Data from our laboratory has defined the first small animal model of norovirus infection: We discovered the first murine norovirus (MNV), MNV-1, and demonstrated its cultivation in macrophages and dendritic cells in vitro. We have now used these unique models to examine norovirus pathogenesis and immunity. We have determined that MNV-1 is infectious orally and induces gastroenteritis, confirming the utility of this virus as a model to study human norovirus pathogenesis. Importantly, we have also determined that primary MNV-1 infection fails to afford protection to re-challenge with homologous virus. Thus, MNV-1 represents a valuable model with which to dissect the pathophysiological basis for the lack of lasting protection to human norovirus infection. Our specific hypothesis is that norovirus infection fails to induce protective mucosal immunity because the virus infects mucosal dendritic cells and prevents their full activation. Specifically, we will determine whether MNV-1 infection directly or indirectly inhibits dendritic cell activation and whether MNV-1 infection stimulates regulatory T cells. Our ultimate goal is to understand how these effects on mucosal dendritic cells prevent their stimulation of protective norovirus immunity and to translate this information into effective vaccine design.