Mechanisms of persistence in Trypanosoma cruzi infection

克氏锥虫感染的持续机制

基本信息

批准号：
9979735
负责人：
Rick L Tarleton
金额：
$ 37.5万
依托单位：
UNIVERSITY OF GEORGIA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-23 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9979735
关键词：
Address Animals Biology CD8-Positive T-Lymphocytes Cell surface Cells Chagas Disease Chronic Clinical Communicable Diseases Cytoplasm DNA Deposition Detection Development Disease Effectiveness Engineering Epitopes Event Exposure to Family Genes Genetic Recombination Goals Immune Immune response Immunity Immunotherapy Infection Infection Control Infection prevention Interferon Type I Interferons Interleukin-1 Invaded Kinetoplast DNA Latin America Length Modeling Molecular Mus Natural Immunity Organism Parasites Pathway interactions Pattern Pattern recognition receptor Play Positioning Attribute Predisposition Preventive vaccine Process Production Protein Family Proteins Regulation Reporting Resolution Role Signal Transduction Site Sterility Stimulus T cell response T-Lymphocyte Epitopes Trypanosoma cruzi United States Vaccination Vaccines Variant Work adaptive immune response adaptive immunity base design experimental study improved insight member pathogen prevent response sensor success trans-sialidase vaccine development vaccine-induced immunity

项目摘要

Abstract The premise of this proposal is that the very early events in immune recognition of a pathogen play a crucial role in its ultimate control and tell us a great deal about the potential for cure or prevention of an infection (via vaccination, for example). Over the past ~30 years we have developed an understanding of the various mechanisms that contribute to the ability of hosts to control T. cruzi infection. We also know that in the vast majority of cases, T. cruzi is very effectively controlled but it is extremely rare for the infection to be totally cleared, thus resulting in clinical disease known as Chagas disease. What remains largely unknown is why the otherwise highly effective immune response generated during T. cruzi infection so often fails to completely resolve the infection. The hypothesis that underlies the work proposed in this application is that the eventual success of T. cruzi is a consequence of the parasite’s ability to invade host cells with minimal triggering of host pattern recognition receptors (PRR) and then elicit responses that are largely focused on highly variant parasite proteins. The combination of these two factors delays and diverts the adaptive immune responses not only at the very beginning of the infection but also at new infection sites within the infected host throughout the infection. The consequence of this situation is the persistence of the infection in most hosts and the susceptibility to reinfection of “immune”, previously infected, or currently infected hosts. In this project we further investigate the mechanisms of detection by and evasion of both innate and adaptive immune responses in T. cruzi infection. We will also manipulate the host:parasite interaction by modifying the parasite targets of potential innate and adaptive immune responses and observing the consequences of these manipulations on the ability of T. cruzi to persist in a natural host and to induce sterile protection. The results of these studies will provide insights on how the chronic persistence of T. cruzi can be prevented, and thus approaches for immunotherapies in persistently infected subjects. These studies will also inform on the potential for development of prophylactic vaccines to prevent T. cruzi infection.

抽象的该提议的前提是，免疫识别病原体的早期事件在IST中起着至关重要的作用最终控制，并告诉我们有关治愈或产生感染的可能性的大量信息（通过疫苗接种，因为例如）。宿主控制T. Cruzi感染的能力。受控的屁股完全清除感染极为罕见，从而导致临床疾病称为Chagas 疾病。克鲁兹感染常常无法压缩。应用是Cruzi的最终成功是寄生虫用细胞侵袭宿主细胞的能力的结果。宿主模式识别受体（PRR）的最小触发和十个反应，这些反应高度重点是变异寄生虫蛋白的组合延迟了适应性免疫反应仅在感染开始时，但在新的感染中也坐落在受感染的宿主内感染。重新感染“免疫”，以前感染或当前感染的宿主。 t. cruzi感染中先天和适应性免疫反应的检测机制还通过修改降压器靶标的含量诱导性免疫免疫来操纵宿主：寄生虫相互作用这些操纵对T. Cruzi坚持自然寄主的能力的响应和观察的后果并诱导无菌保护。可以预防克鲁兹，因此在持续感染的受试者中进行免疫疗法。还可以告知预防性疫苗T. cruzi感染的潜力。