Mechanisms of naturally-acquired immunity to malaria

由恶性疟原虫引起的疟疾仍然是一个重大的公共卫生威胁。世界上最贫穷的人口中每年发生2.25亿多起疟疾病例，仅在非洲每年就夺去近100万儿童的生命。由于许多疟疾流行国家的保健基础设施薄弱，青蒿素类复方疗法和驱虫蚊帐等疟疾控制干预措施的广泛实施受到阻碍。此外，事实证明，恶性疟原虫善于获得并迅速传播抗疟药物的抗药性，而且病媒控制不断受到不可避免的抗药性蚊子出现的威胁。最终，控制、消除甚至根除疟疾的关键工具是有效的疫苗。由于对恶性疟原虫和人类免疫系统之间的相互作用缺乏了解，阻碍了高效疟疾疫苗的开发。重要的是，在恶性疟原虫反复感染后可以获得对疟疾的保护性免疫，但在没有持续暴露的情况下会迅速减弱。最终赋予这种保护的先天性和适应性免疫反应的质量以及导致其低效获得和快速丧失的机制尚不清楚。我们的目标是通过解决这些关键的知识差距，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严格的纵向队列研究，以加深我们对恶性疟原虫和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，我们继续追求五个主要目标：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，其中对恶性疟原虫感染的暴露和对疟疾的保护进行了可靠的评估，2）确定对恶性疟原虫的抗体应答的抗原特异性、功能、动力学和细胞基础，3）确定恶性疟原虫诱导的炎症的调节机制，4）通过系统生物学方法鉴定对疟疾免疫的分子特征，以及5）确定持续无症状恶性疟原虫感染与疟疾风险之间的关系，并阐明这种现象背后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科技大学（USTB）经验丰富的临床医生和科学家团队密切合作而实现的。为了扩大我们的工作范围，并最大限度地利用我们在马里的队列研究中获得的知识，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.克雷格文特尔研究所合作，将强大的测序技术纳入我们在马里的队列研究分析中。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产生了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，并使人们更普遍地了解人类对传染病的免疫反应的机制。

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.