Mucusal and Systemic Immunity, Vaccines and Microbiota Interplay in Humans

描述(申请人提供)：肠道感染是地方性和流行性传染病，仍然困扰着世界各地的主要人群，特别是在发展中国家，也对美国旅行者(包括部署的军事人员)构成风险。疫苗被广泛视为预防和控制地方性和流行性感染的具有成本效益的干预措施。尽管需要开发新的或改进的疫苗来对抗具有重大公共卫生意义的肠道病原体，但由于对在胃肠道复杂环境中系统运行的免疫机制的零散了解，这些疫苗的开发一直受到阻碍。因此，这项拟议的CCHI的中心主题是促进我们对人类粘膜免疫的了解。为此，我们将解决最重要的假设，即系统地和在肠道粘膜中诱导的效应器和调节免疫机制的微妙动态平衡，以及与常驻肠道微生物区系的相互作用，在保护人类免受伤寒方面发挥关键作用。要利用的一些独特资源是在地面制动临床试验中已经收集的样本，涉及在接种减毒伤寒疫苗之前或之后对携带野生型(Wt)伤寒沙门氏菌的志愿者的挑战，包括FDA授权的Ty21 a伤寒疫苗。除了复杂的机制免疫学研究外，由于迅速积累的证据表明正常的微生物区系可能在宿主免疫反应的诱导中发挥主要作用，我们建议极大地扩大在当前CCHI拨款期间就宿主免疫反应与人类肠道微生物区系之间的相互作用进行的开创性研究。同样重要的是，我们将利用最先进的人体肠道粘膜和粘膜活检外植体的最先进的体外器官模型来研究伤寒沙门氏菌与宿主之间的初步相互作用，包括先天免疫和生理后果。最后，我们将在儿童中进行研究，他们主要受伤寒影响，但几乎没有关于Ty21a免疫引起的保护性免疫的信息。由于这项工作的复杂性，我们组建了一个多学科团队，由天然和获得性免疫、疫苗学、粘膜生物学和生理学、临床胃肠病学(具有丰富的内窥镜检查经验)、分子生物学、生物化学、微生物学、基因组学、生物信息学和生物统计学等领域的知名研究人员组成。我们期待这次CCHI将在一个对人类健康非常重要的领域提供急需的信息，并推动急需的改进口服疫苗的开发。

DESCRIPTION (provided by applicant): Enteric infections are endemic and epidemic infectious diseases that still afflict major populations around the world, particularly in developig nations, and also pose risks for US travelers (including deployed military personnel). Vaccines are widely viewed as cost-effective interventions to prevent and control endemic and epidemic infections. In spite of the need to develop new or improved vaccines against enteric pathogens of great public health importance, their development has been impeded by fragmentary understanding of the immunological mechanisms operational systemically and in the complex environment of the Gl tract. Thus, the central theme of this proposed CCHI is to advance our knowledge of human mucosal Immunity. To this end we will address the overarching hypothesis that the delicate homeostasis of effector and regulatory Immunological mechanisms elicited systemically and in the gut mucosa, and the Interplay with the resident gut microbiota, play a critical role in protection from typhoid fever in humans. Some of the unique resources to be utilized are specimens already collected during ground-braking clinical trials involving the challenge of volunteers with wild-type (wt) S. Typhi before or following immunization with attenuated S. Typhi vaccines, including the FDA licensed Ty21 a typhoid vaccine. In addition to sophisticated mechanistic immunological studies, because evidence is rapidly accumulating that the normal microbiota is likely to play a major role in the induction of host's immune responses, we propose to dramatically expand the pioneering studies conducted during the current CCHI grant on the interactions between the host immune responses and the gut microbiota in humans. Equally important, we will utilize state-of-the-art sophisticated in vitro organotypic models of the human intestinal mucosa and mucosal biopsy explants to study the initial interactions between S. Typhi and the host, including innate immunity and physiological consequences. Finally, we will perform studies in children, who are primarily affected by typhoid fever but for whom virtually no information is available on the protective immunity elicited by Ty21a immunization. Because of the complexity of this undertaking, we have assembled a multidisciplinary team consisting of renowned investigators in the fields of innate and adaptive immunity, vaccinology, mucosal biology and physiology, clinical gastroenterology (with extensive experience in performing endoscopies), molecular biology, biochemistry, microbiology, genomics, bioinformatics, and biostatistics. We expect this CCHI to yield much needed information in an area of great importance to human health and to advance the development of much needed improved oral vaccines.