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。每年在世界上最贫穷的人口中发生2.25亿多例疟疾病例，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差，妨碍了广泛实施疟疾控制干预措施，如以青蒿素为基础的联合疗法和驱虫蚊帐。此外，恶性疟原虫已被证明善于获得并迅速传播对抗疟药物的耐药性，而且不可避免地出现的抗杀虫剂蚊子不断威胁着病媒控制。最终，控制、消除甚至根除疟疾的一个关键工具是有效的疫苗。由于对恶性疟原虫与人类免疫系统之间的相互作用了解不足，在一定程度上阻碍了高效疟疾疫苗的开发。重要的是，在反复感染恶性疟原虫后可获得对疟疾的保护性免疫，但在没有持续接触的情况下会迅速减弱。最终提供这种保护的先天和适应性免疫反应的质量，以及它们获得效率低下和迅速丧失的机制，目前尚不清楚。我们的目标是通过解决这些关键的知识空白，为疟疾疫苗的开发提供信息。为此，我们应用免疫学和基因组学技术的最新进展，在疟疾流行地区进行了严格的纵向队列研究，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，定义疟疾免疫的分子和细胞特征，并确定潜在的疟疾疫苗靶点。在2016财年，我们继续追求五大目标：1)从马里正在进行的纵向队列研究中获得高质量的临床数据和生物标本，这些研究可靠地评估了恶性疟原虫感染暴露和对疟疾的保护作用；2)确定恶性疟原虫抗体反应的抗原特异性、功能、动力学和细胞基础；3)确定恶性疟原虫诱导的炎症受到调节的机制；4)通过系统生物学方法确定疟疾免疫的分子特征。5)确定持续无症状恶性疟原虫感染与疟疾风险的关系，并阐明这一现象背后的宿主和寄生虫因素。我们与巴马科科技大学（USTTB）经验丰富的临床医生和科学家团队密切合作，在马里开展了大规模队列研究。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所获得的知识，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，我们正在与J. Craig Venter研究所合作，将强大的基于测序的技术纳入我们在马里的队列研究的分析中。与疟疾临床结果相关的宿主和寄生虫的基因组和转录组特征正在产生关于自然恶性疟原虫感染诱导疟疾免疫的生物学机制的新假设。这一项目和其他正在进行的项目有助于更全面地了解获得和维持对疟疾的免疫力，也有助于深入了解人类对传染病的免疫反应中起作用的机制。

Malaria caused by Plasmodium falciparum remains a major public health threat. Over 225 million cases of malaria occur annually among the world's 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. 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 poorly understood. Our objective is to inform 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, to define molecular and cellular signatures of malaria immunity and to identify potential malaria vaccine targets. In FY 2016 we continued to pursue five main objectives: 1) obtain high quality clinical data and biospecimens from ongoing 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 University of Sciences, Techniques & Technologies of Bamako (USTTB). 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, we have an ongoing 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 of both the host and parasite that correlate with malaria clinical outcomes are yielding new hypotheses regarding the biological mechanisms through which malaria immunity is induced by natural P. falciparum infection. This and other ongoing projects are contributing to a more comprehensive understanding of the acquisition and maintenance of immunity to malaria, and also providing insights into the mechanisms at play in human immune responses to infectious diseases more generally.