Mechanisms of naturally-acquired immunity to malaria

由恶性疟原虫引起的疟疾仍然是一个主要的公共卫生威胁。在世界上最贫穷的人口中，每年发生超过2.25亿疟疾病例，仅在非洲每年就夺去近100万儿童的生命。许多疟疾流行国家的保健基础设施较差，阻碍了广泛实施以青蒿素为基础的联合疗法和驱虫蚊帐等疟疾控制措施。此外，事实证明，恶性疟原虫善于获得并迅速传播对抗疟疾药物的抗药性，而病媒控制不断受到出现抗药性蚊子的必然性的威胁。归根结底，控制、消除甚至根除疟疾的一个关键工具是有效的疫苗，然而临床开发中的候选疫苗充其量只能提供部分保护。对恶性疟原虫和人类免疫系统之间的相互作用缺乏了解，这在一定程度上阻碍了高效疟疾疫苗的开发。重要的是，对疟疾的保护性免疫可在反复感染恶性疟原虫后获得，但在没有持续暴露的情况下迅速减弱。最终给予这种保护的先天和获得性免疫反应的质量以及它们低效获得和快速丧失的机制在很大程度上是未知的。我们的目标是通过解决这些关键的知识差距来帮助疟疾疫苗的开发。为此，我们将免疫学和基因组学技术的最新进展应用于疟疾流行地区严格进行的纵向队列研究，以加深我们对恶性疟原虫与人类免疫系统之间相互作用的理解，并确定疟疾免疫的分子和细胞特征。我们有五个主要目标：1)从马里的纵向队列研究中获得高质量的临床数据和生物标本，在这些研究中，对恶性疟原虫的感染和预防进行了可靠的评估，2)确定了对恶性疟原虫抗体应答的抗原特异性、功能、动力学和细胞基础，3)确定了恶性疟原虫诱导的炎症的调节机制，4)通过系统生物学方法确定了疟疾免疫的分子特征，以及5)确定了持续的无症状恶性疟原虫感染与疟疾风险之间的关系，并阐明了导致这种现象的宿主和寄生虫因素。我们在马里进行的大型队列研究是通过与巴马科大学疟疾研究和培训中心(MRTC)经验丰富的临床医生和科学家团队的密切合作而实现的。为了扩大我们的工作范围，并最大限度地利用我们在马里进行的队列研究获得的知识，我们与寄生虫生物学、基础免疫学、基因组学和计算生物学方面的专家合作。例如，2012年，我们与J.Craig Venter研究所启动了一项新的合作，将强大的基于测序的技术纳入我们在马里的队列研究分析中。与防止疟疾相关的基因组和转录签名可能会产生关于恶性疟原虫自然感染诱导疟疾免疫的生物学机制的新假设。如果成功，这一项目和其他正在进行的项目不仅有可能有助于更好地了解获得和维持对疟疾的免疫力，而且还可以更广泛地深入了解人类对传染病的免疫反应所起的作用机制。

Malaria caused by Plasmodium falciparum remains a major public health threat. Over 225 million cases of malaria occur annually among the worlds poorest populations, claiming the lives of nearly a million children each year in Africa alone. The widespread implementation of malaria control interventions such as artemisinin-based combination therapy and insecticide-treated bed nets is hampered by the poor health-care infrastructure of many malaria-endemic countries. Moreover, P. falciparum has proven adept at acquiring and rapidly spreading resistance to antimalarial drugs, and vector control is constantly threatened by the inevitability of the emergence of insecticide-resistant mosquitoes. Ultimately, a key tool for the control, elimination, or even eradication of malaria is an effective vaccine, yet vaccine candidates in clinical development confer only partial protection at best. The development of a highly effective malaria vaccine has been hindered in part by a poor understanding of the interaction between P. falciparum and the human immune system. Importantly, protective immunity to malaria can be acquired after repeated P. falciparum infections but wanes rapidly in the absence of ongoing exposure. The quality of the innate and adaptive immune responses that ultimately confers this protection and the mechanisms that underlie their inefficient acquisition and rapid loss are largely unknown. Our objective is to aid malaria vaccine development by addressing these critical knowledge gaps. To this end, we apply recent advances in immunology and genomics-based technology to rigorously conducted longitudinal cohort studies in malaria-endemic areas to deepen our understanding of the interaction between P. falciparum and the human immune system and to define molecular and cellular signatures of malaria immunity. We have five main objectives: 1) obtain high quality clinical data and biospecimens from longitudinal cohort studies in Mali in which exposure to P. falciparum infection and protection against malaria are reliably assessed, 2) determine the antigen specificity, function, kinetics and cellular basis of the antibody response to P. falciparum, 3) define the mechanisms by which P. falciparum-induced inflammation is regulated, 4) identify a molecular signature of immunity to malaria through systems biology approaches, and 5) determine the relationship between persistent asymptomatic P. falciparum infection and malaria risk, and elucidate the host and parasite factors that underlie this phenomenon. The large cohort studies we conduct in Mali are made possible through a close collaboration with an experienced team of clinicians and scientists at the Malaria Research and Training Center (MRTC) at the University of Bamako. To expand the scope of our work and to maximize the knowledge gained from our cohort studies in Mali, we collaborate with experts in parasite biology, basic immunology, genomics and computational biology. For example, in 2012 we initiated a new collaboration with the J. Craig Venter Institute to incorporate powerful sequencing-based technologies into the analysis of our cohort studies in Mali. Genomic and transcriptomic signatures that correlate with protection from malaria may yield new hypotheses regarding the biological mechanisms through which malaria immunity is induced by natural P. falciparum infection. If successful, this and other ongoing projects have the potential to contribute not only to a better understanding of the acquisition and maintenance of immunity to malaria, but also to provide insights into the mechanisms at play in human immune responses to infectious diseases more generally.