Mechanisms of persistence in Trypanosoma cruzi infection

摘要 这一提议的前提是病原体的免疫识别的非常早期的事件在其 最终控制和告诉我们许多关于治愈或预防感染的潜力(通过接种疫苗，为 例如)。在过去的30年里，我们已经对各种机制有了深入的了解 寄主控制克氏毛滴虫感染的能力。我们还知道，在绝大多数情况下，克氏支原体非常有效 但感染被完全清除是极其罕见的，从而导致临床上称为恰加斯病的疾病。 疾病。很大程度上仍不清楚的是，为什么在T。 克鲁兹病毒感染往往不能完全解决感染问题。本文中提出的工作所依据的假设 应用是，克氏锥虫的最终成功是这种寄生虫入侵宿主细胞的能力的结果 最小限度地触发宿主模式识别受体(PRR)，然后引发高度关注的反应 变异型寄生虫蛋白。这两个因素的结合延迟和转移了获得性免疫反应，而不是 仅在感染开始时，而且在感染宿主内的新感染部位 感染。这种情况的后果是大多数宿主的感染持续存在，并对 “免疫”、先前感染或当前感染的宿主的再感染。在这个项目中，我们进一步研究了 克氏毛滴虫感染中先天免疫反应和获得性免疫反应的检测和逃避机制。我们会 还可以通过修改潜在的先天免疫和获得性免疫的寄生虫靶标来操纵宿主：寄生虫的相互作用 反应和观察这些操纵对克氏锥虫在自然宿主中持续存在的能力的影响 并诱导无菌保护。这些研究的结果将为T。 克鲁兹是可以预防的，因此可以为持续感染的受试者提供免疫治疗的方法。这些研究将 还通报了开发预防克氏毛滴虫感染的预防性疫苗的潜力。

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.