Elucidation of Pathogenic Mechanisms underlying Norovirus Diarrhea

项目摘要 诺如病毒是急性胃肠炎的主要原因，也是儿童重症的主要原因 全球腹泻我们在2003年发现了鼠诺如病毒（MNV），加速了 通过提供小动物模型和能够进一步理解发病机制， 这些肠道病毒。然而，该模型系统的一个主要限制是野生型实验室 与人相比，小鼠在感染MNV时没有显示出明显的疾病 在免疫活性宿主中有症状的诺如病毒。这限制了该领域的能力， 阐明诺如病毒诱导的事件引起的疾病。然而，应当指出，所有 迄今为止进行的MNV毒力研究使用的是成年小鼠。考虑到人类的 诺如病毒感染在年轻的宿主中更严重，我们假设年轻的小鼠会 也容易感染MNV疾病。我们已经产生了令人兴奋的数据证实， MNV感染导致新生幼崽急性自愈性腹泻，这是一个变革性的发现 诺如病毒领域胃肠道疾病的严重程度受病毒遗传决定因素的调节 并且与肠上皮的病理变化有关， 肠道免疫细胞。我们建议使用这个新的系统来测试我们的工作 肠免疫细胞的感染导致上皮细胞破坏的模型， 随之而来的腹泻我们的主要目标是阐明腹泻的病毒决定因素， 确定感染的关键免疫细胞靶点，并探测病毒与 肠上皮这些目标的整合将使我们能够绘制出关键的病毒宿主 肠道疾病的相互作用。

Project Summary Noroviruses are a major cause of acute gastroenteritis and the leading cause of severe childhood diarrhea globally. Our discovery of murine norovirus (MNV) in 2003 accelerated progress in the field by providing a small animal model and enabling further understanding of the pathogenesis of these enteric viruses. Yet a major limitation of this model system is that wild-type laboratory mice have not been shown to develop overt disease when infected with MNV, in contrast to human norovirus which is symptomatic in immunocompetent hosts. This limits the field’s ability to elucidate norovirus-induced events responsible for disease. It should be noted, however, that all virulence studies of MNV performed to date have used adult mice. Considering that human norovirus infections are more severe in younger hosts, we hypothesized that young mice would likewise be susceptible to MNV disease. We have generated exciting data confirming that oral MNV infection causes acute self-resolving diarrhea in neonatal pups, a transformative discovery for the norovirus field. Gastrointestinal disease severity is regulated by viral genetic determinants and is associated with pathological changes to the intestinal epithelium although the main targets of infection are intestinal immune cells. We propose to use this novel system to test our working model that infection of intestinal immune cells leads to disruption of the epithelium and consequent diarrhea. Our main objectives are to elucidate the viral determinants of diarrhea, define the key immune cell targets of infection, and probe the interactions of the virus with the intestinal epithelium. The integration of these aims will enable us to map key virus-host interactions responsible for intestinal disease.