Mathematical modeling of immune response to malaria

研究总结 疟疾是一种由疟原虫引起的疾病，仍然是最相关的传染病之一。 病例；2013年，超过2亿人患有临床疟疾，超过50万人，主要是儿童， 死于此病。感染始于感染了疟原虫的蚊子向皮肤注射小剂量的孢子虫- 寄生虫是寄生虫的一种特殊的fic型，它通过血液传播到肝脏，感染肝细胞，形成肝脏。 各阶段。几种候选疫苗，包括最新的RTS疫苗，S疫苗，旨在消除孢子虫病。 皮肤、血液或肝细胞中的带状疱疹。然而，这种疫苗的EFfi低成本凸显了这一问题。 缺乏对疟原虫子孢子如何通过宿主免疫消除的基本了解。CD8 T细胞， 淋巴细胞的一个亚群，已被证明在预防临床疟疾中发挥重要作用，通过消除 疟原虫肝脏阶段，特别是在基于辐射减弱子孢子(RAS)的疫苗中，尤其是fi。在生命中使用 成像，我们最近发现，激活的CD8T细胞在感染疟原虫的Hep周围形成簇。 这些细胞群在消除寄生虫过程中起着重要作用。推动形成的机制 以及激活的fiT细胞如何从整个肝脏中消除肝脏阶段 还没有被很好地理解。另一层复杂性出现，因为保护所需的免疫水平取决于 在一种特殊的fic宿主-寄生虫组合上。通过将数学建模和实验相结合，我们将提供 对CD8 T细胞对清除血浆的潜在作用机制的定量见解 昆明种小鼠肝脏发育阶段。我们将通过三个相辅相成的fic目标来提供这样的见解。在特定的fic目标中 1，我们将区分在子孢子周围形成CD8 T细胞簇的不同机制- 感染的肝细胞(T细胞固有的与T细胞外在的)，defiNe T细胞的作用，对无关抗原的特异性fic， 在簇的形成中，并量化T细胞簇大小对哪个肝脏阶段的有效fi频率的影响 都被淘汰了。在特殊fic目标2中，我们将确定肝窦的结构对fi效率的影响。 CD8T寻找罕见的子孢子感染的肝细胞并确定CD8T细胞移动的速度 可以定位感染部位。最后，在特殊fic目标3中，我们将区分不同的机制。 对于更多的记忆CD8 T细胞，需要灭菌保护以防止暴露于疟原虫 约氏原虫子孢子与伯氏疟原虫子孢子的比较。完成这些目标将带来更好的 了解CD8 T细胞如何定位和消除主要外周血中的疟原虫肝脏阶段 组织，肝脏。这一认识有助于设计更有效的基于RAS的fi免疫协议 疟疾疫苗。此外，更深入地了解CD8 T细胞消除感染的机制 对于其他几种基于CD8 T细胞的疫苗的改进也可能有用，例如 那些针对艾滋病毒、丙型肝炎病毒和单纯疱疹病毒的。

Research Summary Malaria, a disease caused by parasites of Plasmodium species, remains one of the most relevant infectious dis- eases; in 2013 over 200 millions of individuals had clinical malaria and over 500,000 individuals, mainly children, died from it. The infection starts when a Plasmodium-infected mosquito injects into the skin a small dose of sporo- zoites, a specific form of the parasite, which travel via the blood to the liver, infect hepatocytes, and form liver stages. Several vaccine candidates, including the most recent RTS,S vaccine, are aimed at eliminating sporo- zoites from the skin, blood, or hepatocytes. However, the low efficacy of such vaccines highlights the problem with lack of basic understanding of how Plasmodium sporozoites are eliminated by host immunity. CD8 T cells, a subset of lymphocytes, have been shown to play an important role in preventing clinical malaria by eliminating Plasmodium liver stages, specifically in radiation attenuated sporozoites (RAS)-based vaccines. Using intravital imaging, we have recently discovered that activated CD8 T cells form clusters around Plasmodium-infected hep- atocytes in mice and that these clusters are important in parasite elimination. Mechanisms driving the formation of such clusters remain poorly defined and how activated CD8 T cells eliminate liver stages from the whole liver is not well understood. Another layer of complexity arises as the level of immunity needed for protection depends on a specific host-parasite combination. By combining mathematical modeling and experiments we will provide quantitative insights into potential mechanisms that explain contribution of CD8 T cells to elimination of Plasmod- ium liver stages in mice. We will provide such insights via three complementary specific aims. In specific Aim 1, we will discriminate between alternative mechanisms of formation of CD8 T cell clusters around sporozoite- infected hepatocytes (T-cell intrinsic vs. T-cell extrinsic), define the role of T cells, specific to irrelevant antigens, in the formation of clusters, and quantify the impact of T cell cluster size on the efficiency at which liver stages are eliminated. In specific Aim 2, we will determine the impact of structure of liver sinusoids on the efficiency of CD8 T search for rare sporozoite-infected hepatocytes and determine the speed at which moving CD8 T cells can localize the site of infection. Finally, in specific Aim 3 we will discriminate between alternative mechanisms for a larger number of memory CD8 T cells required for sterilizing protection against exposure to Plasmodium yoelii sporozoites as compared to Plasmodium berghei sporozoites. Completion of these aims will lead to a better understanding how CD8 T cells localize and eliminate Plasmodium liver stages from one of the major peripheral tissues, the liver. This understanding may help in designing more efficient immunization protocols of RAS-based malaria vaccines. In addition, deeper understanding of the mechanisms by which CD8 T cells eliminate infections at peripheral sites may be also useful for the improvement of several others CD8 T cell-based vaccines such as those against HIV, HCV, and HSV.