Human Cellular Immune Programming Against Invasive Salmonella

项目摘要 侵袭性沙门氏菌病，定义为沙门氏菌感染扩散到远离 胃肠道粘膜，每年造成超过80万人死亡。抗菌素耐药性正在增加 预防沙门氏菌感染，而且没有针对侵袭性非伤寒沙门氏菌(INTS)的疫苗。这个 拟议的研究将评估不同类型沙门氏菌之间的抗原性和表型差异， 尤其是伤寒沙门氏菌，两种主要的INTS菌株，以及典型的非伤寒胃肠炎 沙门氏菌(NTS)影响人类抗原提呈细胞和T细胞免疫防御。中心假说 这个K08应用程序的特点是伤寒沙门氏菌、INTS和典型NTS之间的差异导致不同的 人类细胞免疫激活程序，这可能潜在地解释临床综合征的差异。在……里面 目的1申请人将调查侵袭性和非侵袭性沙门氏菌之间的差异如何影响 人类抗原提呈细胞对两条中枢细胞因子通路的调节。在目标2中，申请者将学习 曾感染伤寒沙门氏菌的志愿者的T细胞特性 交叉反应的T细胞记忆功能对抗整合性T细胞。目标3将涉及对人类差异的分析 两个主要的INTS菌株和典型NTS之间的巨噬细胞激活程序。理解 免疫识别、免疫激活和T细胞记忆特性对抗侵袭的途径 沙门氏菌可能有助于指导针对这种被忽视的感染的合理疫苗设计。 此K08应用程序详细说明了一个全面、综合的5年培训周期，目标是 从申请人现有的免疫学和传染病背景出发，同时开发新的科学 在人类细胞免疫学方面的技能和领导力。申请者K08培训的中心目标是推出 作为被忽视的肠道感染免疫学领域的独立内科科学家和领导者的职业生涯 疾病和疫苗学。该提案还总结了一项强有力的指导和科学培训计划 作为基础性的教育、职业和职业发展活动。将进行K08项目 在马里兰大学疫苗开发中心，一个特殊的研究和 针对沙门氏菌的人类免疫学和疫苗学方面的培训。

Project Summary Invasive Salmonella disease, defined by the spread of Salmonella infection to sites distant from the gastrointestinal mucosa, is responsible for over 800,000 deaths yearly. Antimicrobial resistance is increasing against Salmonella infection, and there are no vaccines against invasive non-typhoidal Salmonella (iNTS). The proposed studies will evaluate how antigenic and phenotypic differences between different types of Salmonella, specifically S. Typhi, the two predominant iNTS strains, and typical gastroenteritis producing non-typhoidal Salmonella (NTS), impact human antigen presenting cell and T cell immune defense. The central hypothesis of this K08 application is that differences between S. Typhi, iNTS, and typical NTS lead to the initiation of different human cellular immune activation programs, which may potentially explain differences in clinical syndrome. In Aim 1 the applicant will investigate how differences between invasive and noninvasive Salmonella influence the regulation of two central cytokine pathways by human antigen presenting cells. In Aim 2, the applicant will study properties of T cells elicited in human volunteers who were previously challenged with S. Typhi, for potential cross-reactive T cell memory functions against iNTS. Aim 3 will involve analysis of differences in human macrophage activation programs between the two predominant iNTS strains and typical NTS. Understanding pathways of immune recognition, immune activation, and properties of T cell memory against invasive Salmonella may help to guide rational vaccine design against this neglected infection. This K08 application details a comprehensive, integrated 5-year training period with the goal of building from the applicant’s existing background in immunology and infectious diseases while developing new scientific skills and leadership in human cellular immunology. The applicant’s central goal for K08 training is to launch a career as an independent physician-scientist and leader in the immunology of neglected enteric infectious diseases and vaccinology. The proposal summarizes a plan for robust mentorship and scientific training, as well as foundational educational, professional, and career development activities. The K08 project will be conducted at the University of Maryland Center for Vaccine Development, an exceptional environment for research and training in translational human immunology against Salmonella, and vaccinology.