Targeting Peyer's Patches To Improve Salmonella Typhi Vaccine Immunogenicity

针对派尔氏集结提高伤寒沙门氏菌疫苗的免疫原性

基本信息

批准号：
9089926
负责人：
Kenneth L. Roland
金额：
$ 23.18万
依托单位：
ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9089926
关键词：
3-Dimensional Address Animal Model Attenuated Bacteria Bypass Cell Count Cell Culture Techniques Cell Maturation Cells Complex Dendritic Cells Development Disease Dose Effector Cell Environment Epithelial Cells Goals Health Heterophile Antigens Human Immune Immune Cell Activation Immune response Immune system Immunoglobulin A Infection Inflammatory Intestines Invaded Left Legal patent Life Lymphoid Follicle Lymphoid Tissue M cell Microbe Modeling Monitor Mouse Strains Mucosal Immune Responses Mus Oral Outcome Parents Population Process Production Recombinant Vaccines Recombinants Recruitment Activity Salmonella Salmonella Vaccines Salmonella enterica Salmonella typhi Salmonella typhimurium Site Staging Structure Structure of aggregated lymphoid follicle of small intestine T-Lymphocyte Testing Tissues Typhoid Fever Typhoid Vaccine Vaccines Work attenuation base cell mediated immune response cost cytokine enteric pathogen gastrointestinal immune activation immunogenic immunogenicity improved killings monocyte neutrophil pathogen research study response tissue culture uptake vector

项目摘要

DESCRIPTION (provided by applicant): The intestinal environment is one in which the host must continually monitor the native bacterial population and evaluate whether any given microbe is friendly and thus should be left alone or is harmful and should be killed. This task is conducted by the mucosal immune system via routine surveillance of the bacterial population by M cells located along the intestine in Peyer's patches. Numerous studies have described the importance of the interaction between the gastrointestinal pathogen Salmonella Typhimurium and the Peyer's patches, including the observation that Peyer's patches are absolutely required to generate mucosal IgA responses to Salmonella. S. Typhimurium preferentially targets this structure for invasion into the host, and invasion results in the production of high levels of pro-inflammatory cytokines, dendritic cell maturation, T cell priming and the initiation of a robust anti-Salmonella immune response. However, this does not occur during infection with S. Typhi, the causative agent of typhoid fever. This has made the development of live attenuated typhoid vaccines difficult, as the immune responses produced by these vaccines are usually weak and short-lived. We have found that S. Typhi is much less efficient at invading Peyer's patches than S. Typhimurium, and thus during the initial stages of infection there is significantly less immune involvement. To address this problem, we will use a variety of strategies to deliver S. Typhi bacteria directly to the M cells on the Peyer's patches in an attempt to stimulate a more robust immune response. Following infection with S. Typhi cells targeted to the Peyer's patches, the activation of immune cells in the Peyer's patches, cytokine production and innate immune effector recruitment will all be monitored and compared to the responses observed with untargeted S. Typhi as well as S. Typhimurium. The strategies that are able to increase the level of immune involvement and activation will be applied to currently existing typhoid vaccine platforms as a means to improve their efficacy.

描述（通过应用程序提供）：肠道环境是宿主必须连续监测本地细菌种群并评估任何给定的微生物是否友好的环境，因此应独自一人或有害并应杀死。该任务是由粘膜免疫系统通过沿佩耶斑块中肠道的M细胞常规监测细菌种群进行的。大量研究描述了胃肠道病原体伤寒沙门氏菌与佩耶尔的斑块之间相互作用的重要性，包括观察到佩耶的斑块绝对需要粘膜对沙门氏菌的粘膜反应。鼠伤寒链球菌优先针对这种结构侵入宿主，侵袭会导致产生高水平的促炎细胞因子，树突状细胞的成熟，T细胞启动以及强大的抗抗乳细胞免疫反应的倡议。但是，这在伤寒链霉菌感染期间不会发生，这是伤寒的真实药物。这使得活伤的伤寒疫苗的发展变得困难，因为这些疫苗通常弱且短暂的疫苗产生的免疫反应。我们发现，鼠伤寒链球菌在入侵佩耶的斑块上的效率要比鼠伤寒链球菌的效率要低得多，因此在感染的初始阶段，免疫受累大大降低。为了解决这个问题，我们将使用各种策略将斑链球菌细菌直接传递到Peyer斑块上的M细胞中，以刺激更健壮的免疫反应。在靶向Peyer斑块的Typhi细胞感染后，将监测Peyer斑块中免疫细胞的激活，细胞因子的产生和先天免疫效应子的募集，并将其与未经靶向的Typhi和Typhi的反应进行比较。能够提高免疫力参与水平和激活水平的策略将应用于当前现有的伤寒疫苗平台，以提高其效率。