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传播到远离 胃肠道粘膜，每年造成超过800，000人死亡。抗生素耐药性正在增加 目前还没有针对侵袭性非伤寒沙门氏菌（iNTS）的疫苗。的 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， 特别是S。伤寒，两种主要的iNTS菌株，以及典型的非伤寒性胃肠炎 沙门氏菌（NTS），影响人类抗原呈递细胞和T细胞免疫防御。核心假设 该K08申请的一个优点是S.伤寒、iNTS和典型的NTS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 目的1申请人将研究侵袭性和非侵袭性沙门氏菌之间的差异如何影响 人抗原呈递细胞对两种中心细胞因子途径的调节。在目标2中，申请人将学习 在先前用S.伤寒，潜在的 交叉反应性T细胞记忆功能对抗iNTS。目标3将涉及分析人类 两种主要iNTS菌株和典型NTS之间的巨噬细胞活化程序。理解 免疫识别途径、免疫激活和T细胞记忆对抗侵袭性 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应用程序详细介绍了一个全面的，综合的5年培训期，目标是建立 从申请人现有的免疫学和传染病背景，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。申请人K08培训的中心目标是启动一个 职业生涯作为一个独立的医生，科学家和领导者在免疫学被忽视的肠道传染病 疾病和疫苗学。该提案还概述了一项强有力的指导和科学培训计划 作为基础教育，专业和职业发展活动。K08项目将在 在马里兰州大学疫苗开发中心， 在翻译人类免疫学对沙门氏菌和疫苗学的培训。

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.