Influence of gut microbiota on vector competence of disease transmitting insects

昆虫传播的疾病（病媒传播）占全球传染病负担的17%以上。这些疾病大多缺乏有效的哺乳动物疫苗或治疗方法，因此严重依赖病媒控制来预防或减少传播。按蚊和采采蝇分别是疟疾和昏睡病传播的两种媒介。目前的病媒控制方法主要涉及使用对环境不利的杀虫剂，并且鉴于在昆虫中观察到的杀虫剂抗性的出现，其效果正在减弱。了解影响媒介-寄生虫传播生物学的机制可以帮助开发新的控制方法。越来越多的证据表明，传播寄生虫的能力（媒介能力）受到媒介先天免疫反应和与本地微生物的关联的影响。蚊子和采采蝇这两种疾病媒介具有不同的生活史和与肠道微生物群的不同关联。先天免疫应答的一个重要组成部分涉及肽聚糖识别蛋白（PGRPs），它识别病原体特异性分子并调节宿主免疫应答，最终清除病原体。我们已经发现，采采蝇和蚊子的PGRP库和功能根据它们不同的生活史和共生关系而变化。我们还发现，原生微生物群通过在宿主免疫和代谢中发挥重要作用来影响媒介的能力。本研究建立在我们前期研究的基础上，并扩展了我们之前的研究结果：1)表征和比较PGRP在按蚊和采采蝇中不同的功能，重点是PGRP- lb和PGRP- ld； 2)研究肠道微生物群对媒介能力的免疫和代谢贡献。实现我们的目标将扩展我们对以下方面的知识：1)促进病媒能力的PGRPs的结构和调控；2)病媒和微生物群之间的代谢相互作用对疾病传播特性的影响。这些发现有可能促进对病媒、共生体和寄生虫之间三方相互作用的认识，并开发破坏病原体传播的新靶点。

Diseases transmitted by insects (vector borne) account for over 17% of the infectious disease burden globally. Most of these diseases lack efficient mammalian vaccines or treatments, and thus heavily rely on vector control to prevent or reduce transmission. Anopheles and tsetse fly are the two vectors involved in malaria and sleeping sickness transmission, respectively. Current vector control methods largely involve the use of insecticides that are environmentally undesirable, and have diminishing efficacy in light of the emergence of insecticide resistance observed in insects. Understanding the mechanisms that influence vector-parasite transmission biology can help develop new control methods. There is growing evidence that the capacity to transmit parasites (vector competence) is influenced by vector innate immune responses and associations with native microbes. The two disease vectors, mosquitoes and tsetse flies, have varying life histories and different associations with gut microbiota. An important component of the innate immune response to pathogens involves Peptidoglycan Recognition Proteins, PGRPs, which recognize pathogen specific molecules and regulate host immune responses that ultimately clear pathogens. We have identified that the PGRP repertoire and functions in tsetse and mosquito vary in accordance with their different life histories and symbiotic associations. We also found that native microbiota influence vector competence through essential roles they play in host immunity and metabolism. This proposal builds on our preliminary studies and expands our previous findings to: 1) characterize and compare PGRP functions that differ in Anopheles and tsetse focusing on PGRP-LB and PGRP-LD and 2) investigate immune and metabolic contribution of the gut microbiota to vector competence. Implementation of our goals will expand our knowledge on 1) the structure and regulation of PGRPs contributing to vector competence, and 2) influence of metabolic interactions between vectors and microbiota on disease transmission traits. These findings have the potential to advance knowledge on tripartite interactions between vectors, symbionts and parasites, and to develop novel targets for disrupting pathogen transmission.