Innate immune responses to malaria liver stage infection

描述（由申请人提供）：疟原虫是疟疾的病原，每年导致近100万人死亡。它们最初以孢子子的形式感染肝脏，然后在肝细胞内复制成肝脏阶段，产生红细胞外裂子，引发有症状的血液阶段感染。这些红细胞前阶段的感染在临床上是沉默的，被认为不会引起明显的先天免疫反应。然而，我们小组和合作者最近的发现表明，红细胞前阶段在肝脏诱导明显的先天免疫反应。这些复杂寄生虫诱导先天免疫反应的机制以及这些反应对寄生虫感染的下游影响仍不清楚。了解对这种真核细胞内病原体的先天免疫反应本身是很重要的，但也是理解由整个寄生虫免疫引起的无菌性适应性免疫发展的关键缺失部分。因此，我们建议确定野生型和减毒型红细胞前疟原虫激活了哪些先天免疫反应，并确定这些先天免疫反应如何影响保护性适应性免疫反应。通过基因表达分析和功能分析，我们发现肝期感染诱导了由I型和II型干扰素（IFN）信号通路介导的先天免疫反应。我们还发现淋巴细胞在感染后几天内浸润肝脏

DESCRIPTION (provided by applicant): Plasmodium species, the etiologic agents of malaria, kill nearly 1 million people annually. They initially infect the liver as sporozoites, then they replicate as liver stages within hepatocytes to generate exoerythrocytic merozoites that initiate symptomatic blood stage infection. These preerythrocytic stages of infection are clinically silent and were thought to not provoke a significant innate immune response. Yet, recent findings from our group and collaborators have shown that preerythrocytic stages induce a pronounced innate immune response in the liver. The mechanisms by which these complex parasites induce an innate immune response and the downstream effects of these responses on parasite infection remain poorly defined. Understanding the innate immune response to this eukaryotic, intracellular pathogen is important in its own right but also a critical missing piece in the puzzl to understand the development of sterilizing adaptive immunity engendered by whole parasite immunizations. Therefore, we propose to identify which innate immune responses are activated by wild-type and attenuated Plasmodium preerythrocytic parasites and to determine how these innate immune responses influence protective adaptive immune responses. Using gene expression analysis and functional assays, we have shown that liver stage infection induces an innate immune response mediated by type I and type II interferon (IFN) signaling pathways. We have also shown that lymphocytes infiltrate the liver within days following infection and that this infiltration is strongly dependent on type I IFN (IFN-1) signaling. Furthermore, this innate response reduces the initial infection. These results indicate a link between IFN-1, lymphocyte recruitment, and subsequent innate parasite elimination. Our preliminary data also shows that this IFN-1 driven innate response shapes the adaptive immune response that is engendered by whole parasite immunizations. This we demonstrate with mice deficient in key IFN-1 signaling molecules, which surprisingly, are better protected by whole parasite immunizations. In this proposal, we intend to further delineate the generation and consequences of an IFN-mediated innate immune response to Plasmodium liver infection. In Aim 1 we will identify the host-parasite interactions that initiate this IFN-mediated innate immune response and identify the cell types in the liver that respond to IFN. In Aim 2 we will characterize cell-specific responses withi the liver following infection and identify cytokine and chemokine receptors that are necessary for innate lymphocyte infiltration. Additionally, we will evaluate the cellular mechanisms by which these innate cells eliminate liver stage parasites. Finally, in Aim 3, we will investigate how IFN-1-mediated signaling influences the development of adaptive immune responses engendered by whole parasite immunizations. Understanding the nature of the early innate immune response will reveal how a complex eukaryotic parasite engages early host immune defenses. Equally important, it will also identify innate molecular pathways to target for improvement of adaptive immune responses after vaccination that aims to protect against malaria infection.