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.

研究综述 疟疾是一种由疟原虫属寄生虫引起的疾病，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， 感染开始时，一只感染了疟原虫的蚊子将小剂量的孢子注射到皮肤上， 寄生虫的一种特殊形式，通过血液进入肝脏，感染肝细胞，形成肝脏 阶段几种候选疫苗，包括最新的RTS，S疫苗，旨在消除孢子， 从皮肤、血液或肝细胞中分离出孢子。然而，这种疫苗的低效率突出了这个问题 缺乏对疟原虫子孢子如何被宿主免疫消除的基本理解。CD 8 T细胞， 淋巴细胞的一个子集，已被证明在预防临床疟疾中发挥重要作用， 疟原虫肝脏阶段，特别是基于辐射减毒子孢子（RAS）的疫苗。使用活体内 通过成像，我们最近发现活化的CD 8 T细胞在疟原虫感染的HepG 2细胞周围形成簇， 在小鼠中的寄生虫细胞，这些集群是重要的寄生虫消除。推动形成的机制 这些集群的定义仍然很差，以及活化的CD 8 T细胞如何从整个肝脏中消除肝脏阶段 并没有得到很好的理解。另一层复杂性是，保护所需的免疫水平取决于 特定的宿主-寄生虫组合通过结合数学建模和实验，我们将提供 对解释CD 8 T细胞对消除Plasmod的贡献的潜在机制的定量见解- 小鼠的肝脏阶段。我们将通过三个互补的具体目标提供这些见解。具体目标 1，我们将区分子孢子周围CD 8 T细胞簇形成的替代机制- 感染的肝细胞（T细胞内源性vs. T细胞外源性），定义T细胞的作用，特异性针对不相关抗原， 在集群的形成，并量化T细胞集群的大小对肝脏分期的效率的影响， 都被淘汰了在具体目标2中，我们将确定肝窦结构对 CD 8 T细胞寻找罕见的子孢子感染的肝细胞，并确定移动CD 8 T细胞的速度 可以定位感染部位最后，在具体目标3中，我们将区分替代机制 对于大量的记忆性CD 8 T细胞来说， 约氏疟原虫子孢子与伯氏疟原虫子孢子的比较。这些目标的实现将导致一个更好的 了解CD 8 T细胞如何定位和消除疟原虫肝脏阶段从一个主要的外周血淋巴细胞， 组织肝脏这种理解可能有助于设计更有效的基于RAS的免疫方案。 疟疾疫苗此外，更深入地了解CD 8 T细胞消除感染的机制 也可用于改善其他几种基于CD 8 T细胞的疫苗， 抗HIV、HCV和HSV的药物。