Mathematical modeling of immune response to malaria

疟疾免疫反应的数学模型

• 批准号: 9238223
• 负责人: Vitaly V. Ganusov
• 金额: $ 31.73万
• 依托单位: UNIVERSITY OF TENNESSEE KNOXVILLE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9238223
• 关键词: Antigens; Attenuated; Automobile Driving; Blood; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Count; Cells; Child; Clinical; Communicable Diseases; Culicidae; Dermal; Detection; Discontinuous Capillary; Disease; Dose; Epitopes; Erythrocytes; Exposure to; Goals; Gold; HIV/HCV; Hepatocyte; Image; Immune response; Immunity; Immunization; Inbred BALB C Mice; Individual; Infection; Injectable; Liver; Lymphocyte Subset; Malaria; Malaria Vaccines; Memory; Movement; Mus; Natural Immunity; Parasites; Parasitic infection; Pattern; Peripheral; Plasmodium; Plasmodium berghei; Plasmodium yoelii; Play; Probability; Protocols documentation; Radiation; Research; Role; Simplexvirus; Site; Skin; Skin Tissue; Specificity; Speed; Sporozoites; Structure; Symptoms; T-Lymphocyte; Tissues; Travel; Vaccines; Vent; Virus Diseases; Walking; Work; base; cell motility; design; experimental study; improved; in vivo imaging; insight; intravital imaging; killings; mathematical model; pathogen; prevent; vaccine candidate

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.

研究摘要 疟疾是由疟原虫寄生虫引起的一种疾病，仍然是最相关的传染病之一 简单的; 2013年，超过200万人患有临床疟疾，超过50万人（主要是儿童） 死于它。当疟原虫感染的蚊子注入皮肤时，感染开始 Zoites，一种特殊形式的寄生虫，通过血液传播到肝脏，感染肝细胞并形成肝脏 阶段。包括最近的RT疫苗在内的几种疫苗疫苗旨在消除孢子 来自皮肤，血液或肝细胞的ZOITE。但是，这种疫苗的效率低下突出了问题 由于缺乏对寄生虫免疫消除如何消除孢子菌的基本了解。 CD8 T细胞， 一部分淋巴细胞已被证明在防止临床疟疾中起着重要作用 疟原虫肝阶段，基于辐射减毒的孢子虫（RAS）的疫苗。使用插入式 成像，我们最近发现激活的CD8 T细胞在疟原虫感染的HEP周围形成簇 小鼠中的atocytes，这些簇在消除寄生虫中很重要。驱动编队的机制 此类簇的定义很差，而活化的CD8 T细胞如何消除整个肝脏的肝脏阶段 不太了解。由于保护所需的免疫力取决于 在特定的宿主寄生虫组合上。通过结合数学建模和实验，我们将提供 对潜在机制的定量见解，这些机制解释了CD8 T细胞对消除质量的贡献的贡献 IUM肝脏阶段。我们将通过三个完整的特定目标提供此类见解。 1，我们将区分CD8 T细胞簇周围形成CD8 T细胞簇的替代机制。 感染的肝细胞（T细胞固有与T细胞外在），定义T细胞的作用，特定于无关的抗原， 在簇的形成中，并量化T细胞簇大小对肝脏阶段的效率的影响 被淘汰。在特殊目标2中，我们将确定生命正弦的结构对 CD8 T搜索稀有的Sporozoite感染的肝细胞，并确定移动CD8 T细胞的速度 可以定位感染部位。最后，在特殊目标3中，我们将区分替代机制 对于大量的存储器CD8 T细胞，用于对暴露于疟原虫暴露的保护需要 Yoelii子孢子与伯氏疟原虫相比。这些目标的完成将导致更好 了解CD8 T细胞如何定位和消除主要外围之一的疟原虫阶段 组织，肝脏。这种理解可能有助于设计基于RAS的更多有效的免疫协议 疟疾疫苗。另外，更深入地了解CD8 T细胞消除感染的机制 在外围部位，外围位置也可能对改善其他几种CD8 T细胞疫苗，例如 那些反对艾滋病毒，HCV和HSV的人。