Defining immunological mechanisms of serovar cross-reactivity to develop broad spectrum protective vaccines for typhoidal and non-typhoidal Salmonella infections in humans

定义血清型交叉反应的免疫学机制，以开发针对人类伤寒和非伤寒沙门氏菌感染的广谱保护性疫苗

• 批准号: 10584484
• 负责人: Marcelo B. Sztein
• 金额: $ 90.67万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-15 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10584484
• 关键词: 3-Dimensional; Address; Advanced Development; Antigen Presentation; Antigen-Presenting Cells; Area; Attenuated; B-Lymphocytes; Bacteremia; Bacteria; Bacterial Infections; Biomedical Engineering; CD8-Positive T-Lymphocytes; Cells; Cellular Immunity; Characteristics; Circulation; Clinical; Cytometry; Data; Dendritic Cells; Development; Disease; Epidemiology; Epigenetic Process; Epithelial Cells; Event; Exposure to; Fever; Food Contamination; Generations; Genetic; Geographic Distribution; Goals; Human; Immune; Immune response; Immunity; Immunologics; In Vitro; Individual; Infection; Ingestion; Innate Immune Response; Intestines; Lead; Macrophage; MicroRNAs; Modeling; Multi-Drug Resistance; Oral; Organism; Organoids; Outcome; Pathway interactions; Peripheral Blood Mononuclear Cell; Phenotype; Play; Predisposition; Public Health; Resistance; Resources; Role; Salmonella; Salmonella infections; Salmonella paratyphi; Salmonella typhi; Salmonella typhimurium; Serotyping; Southeastern Asia; Specimen; System; T cell response; T-Lymphocyte; Technology; Typhoid Fever; Typhoid Vaccine; Vaccinated; Vaccination; Vaccines; Water; adaptive immune response; antimicrobial; cross reactivity; effector T cell; gastrointestinal infection; molecular marker; neutrophil; non-typhoidal Salmonella; passive antibodies; pathogen; pathogenic bacteria; prevent; response; transcriptomics; vaccine access; vaccine candidate; vaccine development; volunteer

ABSTRACT (CETR RP5, Sztein, PL) Infection with Salmonella spp. due to ingestion of contaminated food and water, including typhoidal (caused largely by S. Typhi (ST) and S. Paratyphi A (PA)), as well as non-typhoidal (NTS) and invasive NTS (iNTS) infections are major public health concerns in many areas of the World, including in the U.S. where NTS causes 1.2 million illnesses annually. The rapid increase in multidrug resistance (MDR) and the lack of vaccines against PA, NTS or iNTS have added a new sense of urgency for the development of vaccines against these pathogens, and ideally broad-spectrum vaccines. One of the major obstacles in developing vaccines against Salmonella spp. is that the precise immunological correlates of protection (CoP) against either infection with wild-type (wt) organisms or vaccines remain unknown, in part because ST and PA are human-restricted infections. The use of specimens from volunteers vaccinated and/or challenged with wt ST has begun to uncover immunological T cell-mediated immunity (T-CMI) effector mechanisms which might be associated with clinical outcome following challenge. No similar data is available for PA since the first wt PA challenge has just been performed. A critical gap also remains in our understanding of the mechanisms of antigen presentation for different Salmonella spp., which may underlie the development of effective adaptive T- CMI and B cell responses, as well as the immune responses elicited in the gut microenvironment following exposure to typhoidal and NTS infections. For these reasons, the overall goal of this application is to advance the development of vaccines against PA as well as broad-spectrum vaccines against enteric fevers, iNTS, and NTS, by identifying protective cross- reactive Salmonella spp. humoral, T effector, and regulatory immune responses, both systemically and in the gut microenvironment, and by defining the mechanisms of antigen presentation against ST, PA, iNTS and NTS that impact adaptive immune cell programming. To achieve these goals we will use PBMC from (i) a challenge study with wt PA with known clinical outcomes (e.g., non-disease or disease), (ii) a study with attenuated PA vaccine candidate strain CVD 1902 followed by challenge with wt PA, (iii) in vitro T cell priming systems and (iv) three human intestinal models: (a) bioengineered 3-D organoids, (b) enteroids, and (c) explants to perform the following Aims: Aim 1. Evaluate whether a defined set of B and T cellular responses in circulation are associated with protection from bacteremic infection and/or bacteremia-negative clinical disease (e.g., fever) following an oral challenge with wt PA in humans, and which regulatory mechanisms are involved in generating these responses. Aim 2. Evaluate whether interactions between ST, PA, iNTS and NTS and dendritic cells (DC) lead to the activation of diverse pathways which in turn determine the priming of defined T cell responses. Aim 3. Contrast molecular biomarker changes and function elicited in gut innate immune cells by various Salmonella serovars and the corresponding isogenic vaccine strains.

摘要（Cetr RP5，Sztein，PL） 沙门氏菌属感染。由于摄入受污染的食物和水，包括伤寒 （很大程度上是由S. typhi（ST）和S. Paratyphi A（PA）以及非细类（NTS）和侵入性NTS引起的 （INT）感染是世界许多领域的主要公共卫生问题，包括美国NTS 每年引起120万疾病。多药电阻（MDR）的快速增加和缺乏 针对PA，NTS或INT的疫苗为开发疫苗增添了新的紧迫感 针对这些病原体，以及理想的广谱疫苗。发展的主要障碍之一 针对沙门氏菌属的疫苗。是保护（COP）的精确免疫学关联 野生型（WT）生物或疫苗的感染尚不清楚，部分原因是ST和PA是 人限制感染。使用WT ST疫苗接种和/或挑战的志愿者的标本使用 已经开始发现免疫T细胞介导的免疫（T-CMI）效应器机制，可能是 与临床结果相关。由于第一个wt pa，因此没有类似的数据可用于PA 挑战刚刚进行。我们对我们对机制机制的理解也仍然是一个关键的差距 不同沙门氏菌的抗原表现，这可能是有效自适应T-的发展的基础 CMI和B细胞反应以及肠道微环境中引起的免疫反应之后 暴露于伤寒和NTS感染。 由于这些原因，此应用的总体目标是提高疫苗的开发 PA以及针对肠狂热，INT和NTS的广谱疫苗，通过识别保护性交叉 反应性沙门氏菌属。系统和在 肠道微环境，并通过定义针对ST，PA，INTS和NTS的抗原表现的机制 这会影响适应性免疫细胞编程。为了实现这些目标，我们将使用（i）挑战中的PBMC 用WT PA进行的，具有已知临床结果（例如非疾病或疾病）的研究，（ii）对PA衰减的研究 疫苗候选菌株CVD 1902，然后在WT PA，（III）体外T细胞启动系统和 （iv）三种人肠模型：（a）生物工程的3-D类器官，（b）肠to虫和（c）外植体进行执行 以下目的：目标1。评估循环中定义的B和T细胞反应是否是 与侵害细菌感染和/或菌血症阴性临床疾病的保护有关（例如，发烧） 在人类中对WT PA进行口头挑战，以及哪些监管机制涉及生成 这些回应。 AIM 2。评估ST，PA，INT和NTS和树突状细胞之间的相互作用是否存在 （DC）导致不同途径的激活，从而决定了定义的T细胞反应的启动。 AIM 3。对比分子生物标志物变化并在肠道先天免疫细胞中引起的功能。 沙门氏菌血清射手和相应的同源疫苗菌株。