A Systems Biology Approach to Malaria Immunity

 描述(申请人提供)：疟疾仍然是最致命的传染病之一，每年造成约65万人死亡。与大多数病毒感染不同，儿童通常会有反复的临床发作，但到了成年，住在流行区的大多数人都能免受疾病的侵袭。从受保护的成体中分离出的免疫球蛋白(Ig)分子可以用来被动地将保护传递给幼稚的个体，这表明抗体介导的免疫起着关键作用。在实验模型中，由CD8T细胞和干扰素介导的细胞免疫也被认为对感染的初始肝脏阶段具有保护作用，但这种类型的免疫在自然人类感染期间的意义还很难评估。由于无法控制和定义寄生虫暴露，现场保护性免疫反应的严格分析受到阻碍。动物研究，虽然允许菌株和接种控制，但由于宿主和寄生虫物种的差异，很难应用于人类感染。本研究的目的是系统地评价10名健康志愿者对一次恶性疟原虫(PF)感染和随后三次恶性疟原虫感染的免疫应答，每个人都作为自己的对照。使用人类疟疾挑战模型可以控制寄生虫暴露的时间，因此可以直接监测对感染的早期反应。这10名志愿者将首先接受未受感染的蚊子的挑战，以建立一个基线，然后连续4次接触感染了PF的蚊子。将每天监测临床症状，志愿者将在第一次疟疾涂片阳性时或在第20天(如果当时没有观察到寄生虫)接受标准剂量的Coartem治疗。如果没有观察到寄生虫，将在挑战之前和之后每隔2天收集血液样本进行转录分析、PBMC免疫表型和血浆鉴定，直到治疗或第20天。此外，将在第20±1天收集浆细胞用于免疫球蛋白谱系评估。这项对反复PF感染的临床和免疫反应的系统研究将提供可用于设计更有效的干预和控制策略的见解。

 DESCRIPTION (provided by applicant): Malaria continues to be one of the most virulent infectious diseases and accounts for the death of ~0.65 million people a year. Unlike most viral infections, children usually have repeated clinical episodes, but by adulthood, most individuals living in endemic areas are protected against disease. Immunoglobulin (Ig) molecules isolated from a protected adult can be used to passively transfer protection to naïve individuals indicating a key role for antibody-mediated immunity. Cellular immunity mediated by CD8 T-cells and IFN has also been implicated in protection against the initial liver stages of the infectionin experimental models, but the significance of this type of immunity during natural human infections has been difficult to evaluate. Rigorous analysis of protective immune responses in the field is hindered by an inability to control and define parasite exposure. Animal studies, whil allowing strain and inoculation controls, are difficult to apply to human infections due to differences across host and parasite species. The goal of the present study is to systematically evaluate the immune response to an initial Plasmodium falciparum (Pf) infection and 3 subsequent Pf infections in 10 healthy volunteers, each serving as their own control. The use of the human malaria challenge model allows the timing of parasite exposure to be controlled and therefore the early response to infection can be directly monitored. The 10 volunteers will first be challenged with uninfected mosquitoes to establish a baseline and then 4 sequential exposures to Pf-infected mosquitoes. Clinical symptoms will be monitored daily and the volunteers will be treated with standard dose of Coartem at the first positive malaria smear or on day 20 if no parasites are observed by then. Blood samples will be collected for transcription profiling, PBMC immunophenotyping and plasma characterization prior to and every 2 days after the challenge until treatment or day 20, if no parasites are observed. Additionally, plasma cells will be collected on day 20 ± 1 for Ig repertoire evaluation. This systematic study of the clinical and immune response to repeated Pf infections will provide insights that can be used to design more effective intervention and control strategies.