Perturbations of host cell signaling by a complex hepatotropic pathogen

病原体必须成功地通过其宿主的复杂相互作用网络才能生存。在.期间 疟疾寄生虫肝脏阶段感染，寄生虫通过防止宿主肝细胞死亡和 利用宿主细胞资源进行生长和发育。宿主肝细胞分子信号转导 促进成功的肝期复制的环境尚未阐明，但它具有高度的医学意义 切合实际。在这笔赠款的第一个获奖期内，我们在阐明 疟疾寄生虫依赖的信号通路的数量，并确定关键宿主 寄生虫在进入过程中参与建立允许细胞内复制的环境的受体 和优化发展。我们已经生成了初步数据，表明疟疾寄生虫不能 除了控制常规形式的宿主细胞防御，如细胞凋亡，还必须仔细调节一种铁- 一种依赖性的细胞死亡形式，称为铁下垂，据我们所知，这种疾病以前从未涉及过 寄主对病原体的防御。这项提案旨在充分描述寄生虫可能导致死亡的环境 躲避，以及什么扰动导致野生型寄生虫的死亡。我们将检验这一假设 肿瘤抑制基因P53是感染细胞中铁下垂的调节因子。我们将以我们的数据为基础， 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，我们将以我们最近的发现为基础，即寄生虫选择一部分肝细胞用于 并确定这一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，而不仅仅是对啮齿动物的反应 疟疾感染，但也是对最致命的人类疟疾寄生虫恶性疟原虫的反应，在 部分是通过使用带有人源化肝脏的小鼠的肝细胞。拟议的研究将导致更多 全面了解肝细胞信号转导格局，调节其成败。 疟原虫肝脏阶段。实现我们的目标开启了改变关键主机因素的可能性 可以防止野生型寄生虫发展为有症状的红细胞感染的小分子。 这种基于宿主的预防方法是新颖的，将绕过持续不断的 对标准抗疟疾药物产生抗药性。这一方法进一步得到了以下事实的促进：许多 肝细胞蛋白已经是已知治疗抑制剂的靶点。更详细地了解 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。

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.