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，病原体免疫认知的早期事件在其其其其其其其其上起着至关重要的作用最终控制并告诉我们有关治愈或预防感染的可能性的大量信息（通过疫苗接种，因为例子）。在过去的大约30年中宿主控制克鲁兹感染的能力。我们还知道，在绝大多数情况下，克鲁兹（T. Cruzi）非常有效受控，但完全清除感染极为罕见，从而导致临床疾病称为Chagas 疾病。仍然未知的是为什么在T期间产生的原本有效的免疫反应。克鲁兹感染常常无法完全解决感染。这是基于此中提出的工作的假设应用是Cruzi的事件成功是寄生虫能够入侵宿主细胞的结果宿主模式识别受体（PRR）的最小触发触发，然后引起主要集中于高度重点的反应变体寄生虫蛋白。这两个因素延迟和转移适应性免疫调查的结合而不是仅在感染开始时，但在整个感染宿主内的新感染部位也感染。这种情况的结果是大多数宿主的感染的持续存在，以及对重新感染“免疫”，以前感染或当前感染的宿主。在这个项目中，我们进一步调查了 Cruzi感染中先天性和适应性免疫回报的检测机理和演变的机理。我们将还通过修改潜在的先天和适应性免疫的寄生虫靶标，操纵宿主：寄生虫相互作用响应并观察这些操纵对T. Cruzi坚持自然寄主的能力的后果并诱导无菌保护。这些研究的结果将提供有关T的慢性持久性的见解。可以防止克鲁兹，因此可以在持续感染的受试者中进行免疫疗法。这些研究会还要告知预防性疫苗的开发潜力，以防止克鲁齐感染。