CAREER: Genetic and Molecular Mechanisms of Parasite Infection in Insects

许多寄生虫需要寄生昆虫作为其生命周期的一部分。了解宿主-寄生虫相互作用的生物学，特别是在遗传和分子水平上的分析，是基础研究的一个重要领域，因为我们缺乏对这些相互作用原理的理解。以昆虫为寄主的寄生虫必须克服昆虫的先天免疫防御才能完成其生命周期，包括在宿主体内的发育和传播。这些相互作用的分子机制，以及这些相互作用变异的遗传基础，还没有完全了解。本项目的重点是了解冈比亚按蚊和引起疟疾的恶性疟原虫的宿主-寄生虫相互作用，以提高对宿主-寄生虫基本相互作用的理解。研究者已经将一些宿主遗传变异与宿主中寄生虫生命阶段数量的变异联系起来，表明个体昆虫宿主之间的免疫变化，因此可能存在传播寄生虫的不同能力。本研究人员开发了一种新的计算方法来识别与寄生虫感染相关的其他宿主基因，这使得研究这种遗传变异在安培自然种群中对寄生虫的免疫成为可能。冈比亚，这可以比在实验室人群中进行研究提供更多信息。研究者将在本研究中采用现代基因组学、生物化学和计算方法。该项目将提高我们对昆虫抗寄生虫先天免疫的遗传基础和分子机制的认识，以及更广泛的宿主-寄生虫相互作用。这项研究的一个重要的更广泛的科学和社会影响是提高了对导致疟疾的特定蚊子-寄生虫系统的理解，疟疾每年造成数百万人的痛苦和死亡。遗传分析表明，冈比亚按蚊的遗传变异与蚊子体内疟原虫卵囊的数量有关。鉴定与感染强度变化相关的基因并了解它们如何发挥作用，对于破译昆虫-寄生虫相互作用的遗传和分子基础非常重要。靶向这些基因将为控制寄生虫传播带来新的途径。然而，使用传统方法很难从蚊子基因组中的约3亿个碱基对和约15,000个基因中确定致病突变。在最近的一项重大发现中，首席研究员和同事使用了一种新颖的计算方法，确定了大约1%的An。冈比亚基因组富含与蚊子感染恶性疟原虫相关的基因。本研究项目旨在分析这些新发现的基因组区域，以阐明昆虫-寄生虫相互作用的分子机制。冈比亚种群和来自肯尼亚西部的恶性疟原虫。将系统地进行直接关联研究，以检测与非洲野生冈比亚疟蚊种群中恶性疟原虫感染强度相关的遗传变异。然后在实验室条件和非洲野外条件下确定候选蚊子基因对寄生虫入侵的相对作用。最后，对候选基因的分子机制进行了研究。计算方法、实验室分子功能分析和现场昆虫学研究的结合是解决昆虫-寄生虫相互作用的一套非常强大的工具。这个CAREER项目将整合从K-12到研究生的研究和教育，在本地、国内和国际范围内进行。K-12学生和教师将有机会与研究人员一起学习和参与基因组学研究。将在当地学校和大学举办关于昆虫-寄生虫相互作用的研讨会。还将在肯尼亚恶性疟原虫流行的社区举办教育研讨会。本科生和研究生在研究中扮演着重要的角色，研究项目也为课堂教育提供了材料和资源。最终，将建立一个优秀的研究项目和一个优秀的基因组学课程。

Many parasites require obligatory insect hosts as part of their life cycle. Understanding the biology of host-parasite interactions, particularly at the genetic and molecular levels of analysis, is an important area of basic research because we lack an understanding of the principles of these interactions. Parasites with insect hosts must overcome insect innate immune defenses to be able to complete their life cycles, including development in the host and transmission. The molecular mechanisms underlying these interactions, and the genetic basis for variation in these interactions, are not fully understood. This project focuses on understanding host-parasite interactions in the mosquito Anopheles gambiae and the malaria-causing parasite Plasmodium falciparum to gain improved understanding of fundamental host-parasite interactions. The investigator has linked some host genetic variation with variation in the number of parasite life stages in the host, indicating variable immunity among individual insect hosts and therefore potentially differential ability to transmit the parasite. This researcher has developed a novel, computational approach to identify additional host genes associated with parasite infection, which enables the investigation of such genetic variation in immunity to parasites in natural populations of An. Gambiae, which can be more informative than studies in laboratory populations. The investigator will employ modern genomic, biochemical and computational methods in this study. This project will improve our knowledge base about the genetic basis of, and the molecular mechanisms of insect innate immunity against parasites, and more generally host-parasite interactions. An important broader scientific and societal impact of this study is improved understanding of the specific mosquito-parasite system that causes the disease malaria, which causes suffering and death in millions of people each year.Genetic analyses have demonstrated that genetic variation in Anopheles gambiae is associated with the number of Plasmodium oocysts in mosquitoes. Identifying the genes associated with variation in infection intensity and understanding how they function are important in decoding the genetic and molecular basis of insect-parasite interaction. Targeting these genes will lead to novel approaches in controlling parasite transmission. However, it is difficult to determine causative mutations from ~300 million base pairs and ~15,000 genes in the mosquito genome using traditional approaches. In a recent, significant finding, the Principal Investigator and co-workers used a novel computational approach and identified approximately 1% of the An. gambiae genome that is enriched with genes related to P. falciparum infection in mosquitoes. This research project is aimed at analysis of these newly identified genomic regions to elucidate molecular mechanisms of insect-parasite interaction using the well-characterized An. gambiae populations and P. falciparum parasites from western Kenya. Direct association studies will be systematically conducted to detect genetic variations associated with P. falciparum infection intensity in wild A. gambiae populations from Africa. Then the relative role of the candidate mosquito genes on parasite invasion will be determined under laboratory conditions and in the wild in Africa. Finally, the molecular mechanisms of candidate genes will be investigated. The combination of computational approaches, molecular functional analyses in the laboratory, and field entomology studies is a very powerful set of tools to address insect-parasite interactions. This CAREER project will integrate research and education from K-12 to graduate students, locally, nationally and internationally. K-12 students and teachers will have opportunities to learn and participate in genomics research with the investigators in this study. Seminars on insect-parasite interactions will be provided in local schools and universities. The educational seminars will also be given to the communities in Kenya where P. falciparum infection is endemic. While undergraduate and graduate students play important roles in the research, the research program also provides materials and resources for education in classrooms. Ultimately, an outstanding research program coupled with an excellent genomics curriculum will be established.