Perturbations of host cell signaling by a complex hepatotropic pathogen

病原体必须成功地通过宿主复杂的相互作用网络才能生存。期间 疟疾寄生虫肝脏阶段感染，寄生虫通过防止其死亡来保护其宿主肝细胞， 利用宿主细胞资源用于生长和发育。宿主肝细胞分子信号传导 促进成功的肝脏阶段复制的景观尚未阐明，但它是高度医学 相关的在第一次授予该补助金期间，我们在阐明 疟疾寄生虫所依赖的信号通路的数量，并确定了关键宿主 寄生虫在进入细胞内建立允许细胞内复制的环境时所使用的受体 最佳发展。我们的初步数据表明，疟疾寄生虫 不仅控制宿主细胞防御的常规形式，如凋亡，而且还必须仔细调节铁- 依赖形式的细胞死亡称为ferroptosis，据我们所知，以前从未涉及 宿主对病原体防御。该提案旨在充分描述寄生虫可以在 逃避，以及什么样的扰动导致野生型寄生虫的死亡。我们将测试假设， 肿瘤抑制因子P53是受感染细胞中铁凋亡的调节因子。我们将建立在我们的数据， 表明P53被疟原虫感染抑制，增加P53水平可以消除肝脏 阶段寄生虫。最后，我们将建立在我们最近的发现，寄生虫选择肝细胞的一个子集， 感染，并确定这种选择对建立寄生虫生存的最佳宿主条件的影响。 在整个拟议的实验中，我们将监测肝细胞信号，不仅在响应啮齿动物 疟疾感染，但也应对最致命的人类疟疾寄生虫，恶性疟原虫， 一部分是通过使用来自具有人源化肝脏的小鼠的肝细胞。拟议的研究将导致更多的 全面了解肝细胞信号转导景观，调节成功或死亡， 疟原虫肝脏阶段实现我们的目标为改变关键的东道国因素提供了可能性， 这种小分子可以防止野生型寄生虫发展为有症状的红细胞感染。 这种基于宿主的预防方法是新颖的，并且将避免持续感染的大规模问题。 对标准抗疟药物产生抗药性。这一做法得到了以下事实的进一步支持： 肝细胞蛋白已经是已知治疗抑制剂的靶点。更详细地理解本 由这种重要的细胞内病原体引起的复杂扰动也可能揭示出 肝细胞信号传导

Pathogens must successfully navigate the complex interaction networks of their hosts to survive. During malaria parasite liver stage infection, parasites protect their host hepatocyte by preventing its death and exploiting the host cell resources for growth and development. The host hepatocyte molecular signaling landscape that facilitates successful liver stage replication has not been elucidated, yet it is highly medically relevant. During the first award period of this grant, we have made significant strides towards elucidating a number of signaling pathways upon which the malaria parasite relies and also identified the critical host receptor which parasites engage during entry to establish a permissive environment for intracellular replication and optimal development. We have generated preliminary data that suggests that malaria parasites must not only control conventional forms of host cell defense such as apoptosis, but also must carefully regulate an iron- dependent form of cell death called ferroptosis, which to our knowledge has never before been implicated in host defense against pathogen. This proposal aims to fully delineate the pro-death milieu that the parasite can evade, and what perturbations lead to the demise of the wild-type parasite. We will test the hypothesis that the tumor suppressor P53 is the regulator of ferroptosis in infected cells. We will build on our data which demonstrates that P53 is suppressed by Plasmodium infection, and increasing P53 levels can eliminate liver stage parasites. Finally, we will build on our recent discovery that parasites select a subset of hepatocytes for infection and determine the impact of this selection on establishing optimal host conditions for parasite survival. Throughout the proposed experiments, we will monitor hepatocyte signals not only in response to rodent malaria infection, but also in response to the most deadly human malaria parasite, Plasmodium falciparum, in part by using hepatocytes from a mouse with a humanized liver. The proposed studies will lead to a more comprehensive understanding of the hepatocyte signaling landscape that regulates the success or demise of the Plasmodium liver stage. Accomplishing our aims opens the possibility of altering key host factors with small-molecules that could prevent a wild-type parasite from progressing to symptomatic erythrocyte infection. Such a host-based approach for prophylaxis is novel and will circumvent the massive problem of continuously developing resistance to standard antimalarial drugs. This approach is further fostered by the fact that many hepatocyte proteins are already targets of known therapeutic inhibitors. A more detailed understanding of the complex perturbations elicited by this important intracellular pathogen might also reveal new aspects of hepatocyte signaling.