Reducing malaria transmission with engineered bacteria

描述（由申请方提供）：对抗疟疾这一无法忍受的负担的斗争仅限于使用杀死蚊子媒介的杀虫剂和杀死人体寄生虫的药物。考虑到最近估计感染疟疾的人数超过5亿人（近12人中有1人），迫切需要采用新的手段来防治这一疾病。我们建议开发一种新的策略来防止按蚊传播疟疾寄生虫，该策略基于对这些昆虫肠道中的细菌进行遗传修饰。我们将详细评估两个候选细菌物种（成团泛菌和Asaia sp.）在幼虫和成年蚊子中定植，以及它们从一代垂直传播到下一代的能力。我们将开发强大的方法，从每种细菌中分泌抗疟疾效应蛋白，以确保效应蛋白将到达寄生虫或中肠上皮的预期目标。将评估分泌效应蛋白的不同细菌菌株干扰蚊子中寄生虫发育的功效。使用从产生单一效应物的工程化细菌菌株获得的数据，我们将创建菌株的最佳组合，其组合联合收割机多种效应物以获得最大功效。鉴于这一供资机制的时间框架有限，尽管已在与相关监管机构（美国环保局）进行讨论，但未提议进行实地试验。这项研究预计将导致开发一种新的武器，可与传统的控制战略（药物，杀虫剂，疫苗）结合使用，以对抗疟疾。 公共卫生相关性：疟疾是最致命的传染病之一，估计每年造成200万人死亡。蚊子是传播的必要媒介。该项目将设计新的方法来干扰蚊子传播寄生虫的能力，方法是对蚊子中肠中的细菌进行遗传修饰。

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.