Mechanisms of persistence in Trypanosoma cruzi infection

摘要 这一提议的前提是，病原体的免疫识别中的非常早期的事件在其免疫应答中起着至关重要的作用。 最终控制，并告诉我们很多关于治愈或预防感染的潜力（通过接种疫苗， 示例）。在过去的~30年里，我们已经对各种有助于 寄主对T.克氏感染我们也知道，在绝大多数情况下，T。cruzi非常有效地 控制，但它是非常罕见的感染完全清除，从而导致临床疾病称为恰加斯 疾病在很大程度上仍然未知的是，为什么T. 克氏感染经常不能完全消除感染。本文提出的工作所依据的假设是， T. cruzi是寄生虫侵入宿主细胞的能力的结果， 最小程度地触发宿主模式识别受体（PRR），然后引发主要集中在高度 变异寄生虫蛋白。这两个因素的结合延迟和转移了适应性免疫反应， 不仅在感染的最初阶段，而且在整个感染过程中， 感染这种情况的后果是大多数宿主的感染持续存在， “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 检测和逃避的先天性和适应性免疫反应在T。克氏感染我们将 还通过修饰潜在的先天性和适应性免疫的寄生虫靶来操纵宿主：寄生虫相互作用 反应，并观察这些操作对T. cruzi坚持在一个自然的主机 并诱导无菌保护。这些研究的结果将为T. 可以预防克鲁齐氏病，因此可以预防持续感染受试者的免疫治疗方法。这些研究将 还告知预防性疫苗的发展潜力，以防止T。克氏感染

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.