Human Parasite and Mosquito Determinants of Plasmodium Vivax Transmission

由亚马逊地区的恶性疟原虫和间日疟原虫引起的疟疾是造成 世界范围内巨大的人类苦难和人类经济损失。这里提出的研究的长期目标是通过了解调节疟疾寄生虫从人类宿主传播到蚊子的人类、寄生虫和蚊子因素，为全球疟疾控制做出贡献。尽管自1950年代以来一直在努力根除疟疾，但疟疾的发病率和死亡率已回升至比以往任何时候都高的水平。目前还没有有效的疟疾疫苗。抗药性疟疾不仅在致命的人类疟疾寄生虫恶性疟原虫中很常见，而且还在增加，而且在分布更广泛的人类疟疾寄生虫间日疟原虫中也是如此。我们试图解释的一个关键观察是，为什么感染了间日疟原虫的患者在实验条件下只有效地(-50%)感染了野生捕获的达令按蚊。该项目的中心假设是，人类抗体反应、细胞免疫以及间日疟原虫成熟度和性别比例可能调节寄生虫对蚊子的传染性；不同种类的热带按蚊对间日疟原虫的敏感性不同。这些假设将在以下特定目标中进行检验：1)在有症状和无症状的患者群体中，确定人类体液反应、人类细胞介导的免疫反应、间日疟原虫配子体成熟度和性别比与寄生虫传播达令按蚊之间的贡献和关联；2)评估定植的达令按蚊和非达林吉潜在疟疾媒介蚊子对间日疟原虫感染的易感性；以及3)确定具有自然获得的传播阻断抗体的患者的传播阻断活性的机制。该项目将对影响间日疟原虫在亚马逊低流行地区从人类宿主传播到自然、野生型新热带按蚊媒介的基本机制提供新的见解。

Malaria, caused by both Plasmodium falciparum and P. vivax in the Amazon region, is responsible for enormous human suffering and human economic loss worldwide. The long-term objective of the research proposed here is to contribute towards the global control of malaria by understanding human, parasite and mosquito factors that modulate the transmission of malaria parasites from the human reservoir to mosquitoes. Despite eradication efforts since the 1950s, malaria has rebounded to levels of morbidity and mortality that are higher than ever. There is no effective malaria vaccine. Drug-resistant malaria is common and increasing not only in the lethal human malaria parasite, Plasmodium falciparum but also in the even more widespread human malaria parasite, P. vivax. A key observation we seek to explain is why patients infected with P. vivax that have patent gametocytemia only inefficiently (-50%) infected wild-caught Anopheles darlingi mosquitoes under experimental conditions. The central hypotheses ofthis project are that that human antibody responses, cell-mediated immunity, and P. vivax maturity and sex ratios may modulate parasite infectivity to mosquitoes; and that different species of neotropical anopheles mosquitoes differ in their sensitivity to P. vivax. These hypotheses will be tested in the following Specific Aims: 1) To determine the contributions and associations ofhuman humoral responses, human cell-mediated immune responses, and P. vivax gametocyte maturity and sex ratio with parasite transmission to Anopheles darlingi, in both symptomatic and asymptomatic patient populations; 2) To assess the susceptibility of colonized Anopheles darlingi and non-An darlingi potential malaria vector mosquitoes to infection by Plasmodium vivax; and 3) To determine mechanisms of transmission blocking activity in patients with naturally acquired transmission blocking antibodies. This project will provide new insights into fundamental mechanisms affecting the transmission of P. vivax from the human reservoir to natural, wild type neotropical Anopheles mosquito vectors in the Amazonian hypoendemic setting.