Human Parasite and Mosquito Determinants of Plasmodium Vivax Transmission

在亚马逊地区，由恶性疟原虫和间日疟原虫引起的疟疾是造成 世界各地的巨大人类痛苦和人类经济损失。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经回升到比以往任何时候都高的水平。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，而且在更广泛的人类疟疾寄生虫间日疟原虫中也很常见。我们试图解释的一个关键观察结果是，为什么感染间日疟原虫的患者在实验条件下只能无效地（~ 50%）感染野生捕获的达氏按蚊。该项目的中心假设是，人类抗体反应，细胞介导的免疫，以及间日疟原虫的成熟度和性别比例可能会调节寄生虫对蚊子的感染性;不同种类的新热带按蚊对间日疟原虫的敏感性不同。这些假设将在以下具体目的中进行检验：1）确定在有症状和无症状的患者人群中，人类体液应答、人类细胞介导的免疫应答、间日疟原虫配子体成熟度和性比与疟原虫传播达氏按蚊的贡献和关联; 2）评估定殖达林按蚊和非达林按蚊潜在疟疾媒介蚊子对间日疟原虫感染的敏感性;和3）确定具有天然获得的传播阻断抗体的患者中传播阻断活性的机制。该项目将为影响间日疟原虫从人类宿主传播到亚马逊河低地方病环境中的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.