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是经口感染的并诱导胃肠炎， 证实了该病毒作为研究人诺如病毒发病机制的模型的实用性。重要的是我们有 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，可以用来剖析缺乏免疫反应的病理生理学基础。 持久保护人类诺如病毒感染。我们的具体假设是诺如病毒感染不能 诱导保护性粘膜免疫，因为病毒感染粘膜树突状细胞， 他们的全面激活。具体地说，我们将确定MNV-1感染是否直接或间接地抑制 树突状细胞活化和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它们刺激保护性诺如病毒 并将这些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.