Role of Intestinal Bacteria in Human Norovirus Infection

 描述(申请人提供)：诺如病毒是全世界流行性和散发性胃肠炎的重要原因。它们是美国儿童严重腹泻的主要原因，也是发展中国家儿童严重腹泻的主要原因。因此，开发有效的疫苗和治疗方法是当务之急。这一发展的主要障碍是无法培养人类诺如病毒。为了克服这一障碍，我们有两项了不起的发现--(1)人类诺如病毒感染B细胞；(2)它们需要肠道细菌才能获得最佳感染。使用成熟的诺沃克病毒感染小鼠模型，我们在体内环境中验证了这两种感染特征。此外，这两个发现都为理解诺沃克病毒的发病机制和制定有效的抗击感染策略提供了根本上的重要线索。我们推测，人类诺如病毒与肠腔内的共生细菌和病毒相互作用：细菌复合体通过肠道上皮细胞转运，以访问潜在的B细胞靶点。在这个过程中，共生细菌应该被粘膜免疫细胞识别，并刺激产生耐受的微环境。在这种环境下，应该通过一种称为旁观者抑制的过程来遏制对病毒的免疫反应的发展。这一模型得到了长期存在的知识的支持，即诺沃克病毒感染是非炎症性的，它们未能诱导强大的保护性免疫。了解这种明显的弱免疫原性的基础是设计有效的治疗方法的关键。因此，拟议研究的目的是阐明肠道细菌促进诺沃克病毒感染B细胞的机制(特定目标1)；以及这种相互作用的免疫后果(特定目标2)。

 DESCRIPTION (provided by applicant): Noroviruses are a significant cause of epidemic and sporadic gastroenteritis worldwide. They are the leading cause of severe childhood diarrhea in the United States and a major cause of severe childhood diarrhea in developing nations. Thus, development of effective vaccines and therapeutics is a critical need. The major barrier to this development has been the inability to culture human noroviruses. We have made two remarkable discoveries to overcome this obstacle - (1) human noroviruses infect B cells; and (2) they require enteric bacteria for optimal infection. Using the well-developed murine model of norovirus infection, we have validated both of these features of infection in an in vivo setting. Moreover, both of these findings provide fundamentally important clues to understanding norovirus pathogenesis and to developing effective strategies to combat infection. We speculate that human noroviruses interact with commensal bacteria in the gut lumen and virus:bacteria complexes are transcytosed across the intestinal epithelium in order to access the underlying B cell targets. During this process, the commensal bacteria should be recognized by mucosal immune cells and stimulate a tolerogenic microenvironment. In this environment, development of immune responses to the virus should be curbed through a process termed bystander suppression. This model is supported by the long- standing knowledge that norovirus infections are noninflammatory and they fail to elicit robust protective immunity. Understanding the basis for this apparent weak immunogenicity is key to designing effective treatment approaches. The objectives of the proposed research are thus to elucidate the mechanism by which enteric bacteria facilitate norovirus infection of B cells (Specific Aim 1); and the immune consequences of this interaction (Specific Aim 2).