Lack of protective immunity to murine norovirus infection

人类诺如病毒属杯状病毒科，是引起非细菌性流行性胃肠炎的主要病原 国际吧原发性人诺如病毒感染不会引起持久的保护性免疫，这一事实可能 严重影响疫苗接种策略的有效性。我们的长期目标是阐明机制， 哪些诺如病毒避免了保护性免疫的诱导， 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 或者控制它们的免疫反应，因为以前没有小动物模型或细胞 感染的培养系统。来自我们实验室的数据定义了第一个诺如病毒的小动物模型 感染：我们发现了第一个鼠诺如病毒（MNV），MNV-1，并证明了它的培养， 巨噬细胞和树突状细胞。我们现在已经使用这些独特的模型来检查诺如病毒 发病机制和免疫。我们已经确定MNV-1是经口感染的，并且与 诱导腹泻、肠道炎症和绒毛钝化，证实了该病毒作为模型的实用性 研究诺如病毒的致病机制。重要的是，我们还确定了原发性MNV-1感染 不能提供对同源病毒再攻击的保护。因此，MNV-1代表了一个有价值的模型， 从而剖析对人类诺如病毒感染缺乏持久保护的病理生理学基础。 我们的特定假设是诺如病毒感染未能诱导保护性粘膜免疫 因为病毒感染粘膜树突细胞并阻止其完全激活。具体来说，我们将 确定MNV-1感染是否直接或间接抑制树突状细胞活化以及MNV-1是否 感染刺激调节性T细胞。我们的最终目标是了解这些对粘膜的影响， 树突状细胞阻止它们对保护性诺如病毒免疫的刺激，并将该信息翻译成 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 is associated with the induction of diarrhea, intestinal inflammation, and villous blunting, 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.