Role of Intestinal Bacteria in Human Norovirus Infection

肠道细菌在人类诺如病毒感染中的作用

基本信息

批准号：
9416071
负责人：
Stephanie M Karst
金额：
$ 36.88万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-02-16 至 2020-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9416071
关键词：
Antibiotics Antibodies Antigens Antiviral Agents Autoimmune Process B-Lymphocytes Bacteria Binding Biological Models Blood Group Antigens Bystander Suppression Carbohydrates Cell Culture System Cells Charge Childhood Clinical Complex Cytokine Activation Data Developing Countries Development Diarrhea Disease Outbreaks Enteral Enterobacteriaceae Environment Epidemic Epithelial Cells Excision Exclusion Filtration Gastroenteritis Genetic Polymorphism Goals Heterophile Antigens Human Human poliovirus Immune Immune response Immunity Immunoglobulin A Immunologic Adjuvants Immunosuppression In Vitro Infection Inflammation Intestinal Secretions Intestines Knowledge Life Cycle Stages Ligands Mediating Modeling Molecular Mouse Mammary Tumor Virus Mucous Membrane Mus Norovirus Organism Pathogenesis Positioning Attribute Predisposition Primary Infection Process Regulatory T-Lymphocyte Reovirus Research Role Series System Testing Therapeutic Treatment Efficacy United States Vaccines Viral Virion Virus Virus Diseases Work antiviral immunity base combat commensal bacteria cytokine design effective therapy experimental study foodborne gut bacteria immunogenicity immunoregulation improved in vivo infected B cell insight intestinal epithelium microbial mouse model novel practical application prevent public health relevance response stool sample transcytosis vaccine efficacy vector

项目摘要

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).

描述（由申请人提供）：诺如病毒是全球流行性和散发性胃肠炎的重要原因，它们是美国严重儿童腹泻的主要原因，也是发展中国家严重儿童腹泻的主要原因。治疗是这一发展的主要障碍是无法培养人类诺如病毒，我们已经做出了两项重大发现来克服这一障碍 - (1) 人类诺如病毒感染 B 细胞； (2)它们需要肠道细菌来实现最佳感染。利用成熟的诺如病毒感染小鼠模型，我们在体内验证了这两个感染特征。此外，这两项发现为了解诺如病毒提供了根本性的重要线索。我们推测人类诺如病毒与肠腔中的共生细菌相互作用，并且病毒：细菌复合物在肠上皮细胞中转胞吞，以进入潜在的 B 细胞。在此过程中，共生细菌应被粘膜免疫细胞识别并刺激耐受性微环境，在这种环境中，应通过称为旁观者抑制的过程来抑制对病毒的免疫反应。 - 众所周知，诺如病毒感染是非炎症性的，并且无法引发强大的保护性免疫，了解这种明显的弱免疫原性的基础是设计有效治疗方法的关键。因此，本研究的目的是阐明其机制。肠道细菌促进诺如病毒感染 B 细胞（具体目标 1）；以及这种相互作用的免疫后果（具体目标 2）。