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（由申请人提供）：肠道环境是宿主必须持续监测本地细菌种群并评估任何给定微生物是否是友好的（因此应该被保留）或者是有害的（应该被杀死）的环境。大量研究描述了胃肠道病原体鼠伤寒沙门氏菌和鼠伤寒沙门氏菌之间相互作用的重要性。派尔氏斑，包括观察到派尔氏斑是产生针对沙门氏菌的粘膜 IgA 反应所必需的。鼠伤寒沙门氏菌优先针对该结构入侵宿主，并且入侵导致产生高水平的促炎细胞因子、树突状细胞。然而，在感染伤寒沙门氏菌（伤寒沙门氏菌的病原体）期间，这种情况不会发生。这使得减毒活伤寒疫苗的开发变得困难，因为这些疫苗产生的免疫反应通常较弱且短暂。我们发现伤寒沙门氏菌入侵派尔斑的效率远低于鼠伤寒沙门氏菌。，因此在感染的初始阶段，免疫参与显着减少。为了解决这个问题，我们将使用多种策略将伤寒沙门氏菌直接递送至派尔氏集结上的 M 细胞。在用针对派尔氏斑的伤寒沙门氏菌细胞感染后，尝试刺激更强大的免疫反应，对派尔氏斑中免疫细胞的激活、细胞因子的产生和先天免疫效应子的招募都将进行监测，并与观察到的反应进行比较。能够提高免疫参与和激活水平的非靶向伤寒沙门氏菌和鼠伤寒沙门氏菌的策略将应用于当前现有的伤寒疫苗平台，作为提高其功效的手段。