Lack of protective immunity to murine norovirus infection

描述(申请人提供)：杯状病毒科中的人类诺如病毒是全球非细菌性流行性胃肠炎的主要原因。原发人类诺沃克病毒感染不会引起持久的保护性免疫，这一事实可能会极大地影响疫苗接种策略的效果。我们的长期目标是阐明诺如病毒避免诱导保护性免疫的机制，最终将这一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或控制它们的免疫反应知之甚少，因为以前还没有小动物模型或细胞培养系统的感染。我们实验室的数据定义了第一个诺沃克病毒感染的小动物模型：我们发现了第一个小鼠诺沃克病毒(MNV)MNV-1，并在体外证明了它在巨噬细胞和树突状细胞中的培养。我们现在已经使用这些独特的模型来研究诺沃克病毒的发病机制和免疫。我们已经确定MNV-1具有口腔传染性并引起胃肠炎，证实了该病毒作为研究人类诺如病毒致病机制的模型的实用性。重要的是，我们还确定，MNV-1的原发感染不能提供与同源病毒重新挑战的保护。因此，MNV-1代表了一个有价值的模型，可以用来剖析缺乏对人类诺沃克病毒感染的持久保护的病理生理学基础。我们的特定假设是，诺沃克病毒感染未能诱导保护性黏膜免疫，因为该病毒感染粘膜树突状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的激活，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它们对保护性诺沃克病毒免疫的刺激，并将这些信息转化为有效的疫苗设计。 公共卫生相关性：杯状病毒科中的人类诺如病毒是全世界非细菌性流行性胃肠炎的主要原因，但感染不会产生持久的保护作用。我们的长期目标是阐明诺沃克病毒感染避免诱导保护性免疫的机制，最终将这一知识转化为成功的疫苗接种策略。我们的特定假设是，诺沃克病毒感染粘膜树突状细胞导致这些细胞的部分激活，从而诱导调节性免疫反应。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Human noroviruses in the Caliciviridae family are the major cause of non-bacterial epidemic gastroenteritis worldwide but infection does not induce lasting protection. Our long term goal is to elucidate the mechanisms by which norovirus infection avoids the induction of protective immunity, ultimately translating this knowledge into successful vaccination strategies. Our specific hypothesis is that norovirus infection of mucosal dendritic cells results in a partial activation of these cells leading to the induction of regulatory immune responses.