A protective role for IL-17 in blood-stage malaria

描述（由申请人提供）：原生动物寄生虫疟原虫是疟疾的病原体，疟疾仍然是当今世界最突出的公共卫生挑战之一。该项目的总体目标是检查和确定白细胞介素（IL）-17在抗疟原虫免疫应答过程中的潜在保护作用。我们使用IL-17 RA缺陷小鼠的初步研究表明，这些小鼠易受约氏疟原虫17 X感染，其特征是寄生虫负荷迅速增加，贫血发作早，IL-12和IFN-γ缺乏。在感染的急性阶段，约氏疟原虫17 X的产生和死亡，尽管约氏疟原虫17 X感染在野生型小鼠中是非致死性的。此外，脾脏表面 从IL-17 RA缺陷型小鼠分离的树突状细胞表达的主要组织相容性II类分子的量低于来自野生型小鼠的树突状细胞。基于这些发现，我们假设IL-17信号传导的缺乏导致树突状细胞功能受损，并且无法建立保护性免疫应答以控制这种感染。我们建议（目的1）确定约氏疟原虫17 X感染后IL-17的缺乏是否改变树突状细胞表型，以确定树突状细胞对观察到的表型的贡献程度。此外，我们建议（目的2）确定是否IL-17 RA缺陷型小鼠可以从他们的致命表型拯救。从所提出的实验中获得的结果将定义IL-17在疟原虫感染后增强保护性TH 1应答中的作用，通过创建能够诱导IL-17作为诱导更强的寄生虫特异性TH 1应答的手段的疫苗制剂，提供作为抗疟疾疫苗的一部分增强保护性免疫的新策略。

DESCRIPTION (provided by applicant): The protozoan parasite Plasmodium is the causative agent of malaria, which remains one of the most prominent public health challenges in the world today. The overall goal of this project is to examine and define the potential protective roles of interleukin (IL)-17 during an immune response against Plasmodium. Our preliminary studies using IL-17RA-deficient mice indicate that these mice are susceptible to Plasmodium yoelii 17X infection, characterized by a rapid increase in parasite burden, earlier onset of anemia, deficiency in IL-12 and IFN-?? production, and death during the acute stage of the infection, although P. yoelii 17X infection is non-lethal in wild-type mice. Additionally, surfaces of splenic dendritic cells isolated from IL-17RA-deficient mice expressed reduced amounts of major histocompatibility class II molecules than dendritic cells from wild-type mice. Based on these findings, we hypothesize that the absence of IL-17 signaling results in impaired dendritic cell function and an inability to mount a protective immune response to control this infection. We propose to (Aim 1) determine whether the absence of IL-17 alters dendritic cell phenotype after P. yoelii 17X infection in order to identify the extent to which dendritic cells contribute to the observed phenotype. Additionally, we propose to (Aim 2) determine whether IL-17RA-deficient mice can be rescued from their lethal phenotype. Results obtained from the proposed experiments will define the roles of IL-17 in enhancing a protective TH1 response after Plasmodium infection, offering new strategies to enhance protective immunity as part of anti-malarial vaccines by creating vaccine formulations that are able to induce IL-17 as a means of inducing a stronger parasite-specific TH1 response.