Mucusal and Systemic Immunity, Vaccines and Microbiota Interplay in Humans

人类粘膜和系统免疫、疫苗和微生物群的相互作用

• 批准号: 8835015
• 负责人: Marcelo B. Sztein
• 金额: $ 269.62万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-18 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8835015
• 关键词: Address; Advanced Development; Affect; Antigens; Area; Attenuated; Biochemistry; Bioinformatics; Biology; Biometry; Biopsy; Biostatistics Core; Characteristics; Child; Clinical; Clinical Trials; Communicable Diseases; Complex; Data; Developing Countries; Development; Disease; Endoscopy; Enteral; Environment; Epidemic; Epithelial; Epithelial Cells; Equilibrium; Event; Exposure to; Fostering; Gastroenterology; Generations; Genomics; Goals; Grant; Health; Homeostasis; Human; Immune response; Immune system; Immunity; Immunization; In Vitro; Infection; Inflammatory; Intestinal Mucosa; Intestines; Knowledge; Licensing; Life; Link; Mediating; Mediator of activation protein; Microbiology; Military Personnel; Modeling; Molecular Biology; Mucosal Immune Responses; Mucosal Immunity; Mucous Membrane; Natural Immunity; Oral; Organism; Pattern recognition receptor; Physiological; Physiology; Play; Population; Predisposition; Production; Public Health; Research Personnel; Research Project Grants; Resistance; Resources; Risk; Role; Salmonella; Specimen; T-Cell Activation; Time; Toll-like receptors; Ty21a typhoid vaccine; Typhoid Fever; Typhoid Vaccine; Vaccinated; Vaccination; Vaccines; adaptive immunity; arm; combat; cost effective; effective intervention; enteric pathogen; exhaustion; experience; gut microbiota; improved; member; microbial; microbial community; multidisciplinary; oral vaccine; pathogen; prevent; programs; response; trafficking; transmission process; vaccinology; volunteer

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.

描述（由申请人提供）：肠道感染是流行和流行感染性疾病，这些疾病仍然困扰着世界各地的主要人群，尤其是在发展中国家中，还为美国旅行者（包括部署的军事人员）带来了风险。疫苗被广泛视为具有成本效益的干预措施，以预防和控制流行和流行病。尽管有必要针对具有极大的公共健康重要性的肠道病原体开发新的或改进的疫苗，但由于对免疫机制的零散理解，在GL道的复杂环境中，它们的发育受到了阻碍。因此，该提议的CCHI的中心主题是提高我们对人类粘膜免疫的了解。为此，我们将解决以下总体假设：效应子和法规免疫机制的微妙稳态以及与常驻肠道微生物群的相互作用在人类免受人伤寒中的保护中起着至关重要的作用。一些独特的资源是在刹车临床试验期间已经收集的标本，涉及野生型（WT）S。typhi志愿者的挑战，或者在接受衰减的Typhi疫苗免疫之前或之后，包括FDA许可的Ty21 Ty21 Ty21 typhoid疫苗。除了复杂的机理免疫学研究外，由于证据迅速积累，表明正常的微生物群可能在诱导宿主的免疫反应中起主要作用，因此我们建议大幅度扩展当前CCHI在当前CCHI赠款中对宿主免疫反应之间的相互作用的开拓性研究，而host免疫反应与GUT Microbobiota之间的相互作用。同样重要的是，我们将利用人类肠粘膜和粘膜活检外植体的最先进的体外细胞型模型来研究Typhi和宿主之间的初步相互作用，包括先天免疫和生理后果。最后，我们将对儿童进行研究，这些儿童主要受伤寒影响，但实际上没有关于TY21A免疫引起的保护性免疫的信息。 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.我们希望这种CCHI能够在对人类健康非常重要的领域中产生急需的信息，并促进急需改善的口服疫苗的开发。