Reducing malaria transmission with engineered bacteria

描述(申请人提供)：与疟疾无法忍受的负担作斗争仅限于使用杀死蚊媒的杀虫剂和杀死人体寄生虫的药物。考虑到最近的估计数字显示感染疟疾的人数超过5亿(几乎每12人中就有1人感染)，迫切需要引入新的手段来对抗这种疾病。我们建议开发一种新的策略，以防止疟疾寄生虫通过按蚊传播，这是基于对寄生在这些蚊子肠道中的细菌进行基因改造。我们将对两个候选细菌种(Pantoea agregans和Asaia sp.)的能力进行详细的评估。使幼虫和成年蚊子定居，并使它们能够从一代垂直传播到下一代。我们将开发强大的方法来分泌每个细菌物种的抗疟疾效应器蛋白，以确保效应器蛋白将到达寄生虫或中肠上皮上预定的目标。将评估分泌效应蛋白的不同细菌菌株干扰蚊子体内寄生虫发展的效果。使用从产生单一效应器的工程细菌菌株获得的数据，我们将创造出将多个效应器结合在一起以实现最大疗效的菌株的最佳组合。鉴于这一供资机制在时间范围内受到限制，尽管与相关监管机构(美国环保局)的讨论已经在进行中，但没有提议进行实地试验。这项研究有望开发出一种可与传统控制策略(药物、杀虫剂、疫苗)结合使用的新型武器，以抗击疟疾。 与公共卫生相关：疟疾是最致命的传染病之一，每年估计导致200万人死亡。蚊子是传播的必备媒介。该项目将设计新的方法来干扰蚊子传播寄生虫的能力，方法是对蚊子中肠内的细菌进行基因改造。

DESCRIPTION (provided by applicant): The fight against the intolerable burden of malaria is restricted to the use of insecticides that kill the mosquito vector and drugs that kill the parasite in humans. Considering that recent estimates place the number humans infected with malaria at over 500 million (nearly 1 in 12 humans), the introduction of new means to counter the disease is urgently needed. We propose to develop a novel strategy to prevent the spread of malaria parasites by anopheline mosquitoes, based on genetic modification of bacteria that inhabit the gut of these insects. We will evaluate in detail the ability of two candidate bacterial species (Pantoea agglomerans and Asaia sp.) to colonize larval and adult mosquitoes and their ability to be transmitted vertically from one generation to the next. We will develop robust methods to secrete antimalarial effector proteins from each bacterial species to ensure that the effector proteins will reach the intended targets on the parasite or on the midgut epithelium. Different bacterial strains that secrete effector proteins will be evaluated for their efficacy to interfere with parasite development in the mosquito. Using the data obtained from engineered bacterial strains producing single effectors, we will create an optimal combination of strains that combine multiple effectors for maximum efficacy. Given that this funding mechanism is restricted in its time frame, no field trials are proposed although discussions with the relevant regulatory agency (US-EPA) are already underway. This research is expected to lead to the development of a novel weapon that can be used in combination with traditional control strategies (drugs, insecticides, vaccines) to combat malaria. PUBLIC HEALTH RELEVANCE: Malaria is one of the deadliest infectious diseases and kills an estimated 2 million persons every year. The mosquito is the obligatory vector for transmission. This project will devise new ways to interfere with the mosquito capacity to transmit the parasite, by genetically modifying bacteria that live in the mosquito midgut.