CAREER: Genetic and Molecular Mechanisms of Parasite Infection in Insects

许多寄生虫需要强制性的昆虫宿主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分析水平上，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。带有昆虫宿主的寄生虫必须克服昆虫的固有免疫防御，才能完成它们的生命周期，包括在宿主中的发育和传播。这些相互作用背后的分子机制，以及这些相互作用中变异的遗传基础，还没有完全被理解。这个项目的重点是了解冈比亚按蚊和导致疟疾的寄生虫恶性疟原虫中宿主和寄生虫的相互作用，以更好地了解宿主和寄生虫的基本相互作用。研究人员将一些寄主的遗传变异与寄主中寄生虫生活阶段的数量的变化联系起来，这表明个体昆虫之间的免疫力不同，因此可能存在传播寄生虫的能力差异。这位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额外宿主基因，这使得能够在自然种群中调查对寄生虫免疫的这种遗传变异。冈比亚，这可能比在实验室种群中的研究更有信息量。在这项研究中，研究人员将使用现代基因组学、生化和计算方法。这个项目将改善我们关于昆虫对寄生虫的天然免疫的遗传基础和分子机制的知识基础，以及更广泛的宿主与寄生虫的相互作用。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-寄生虫系统的了解，疟疾每年导致数百万人遭受痛苦和死亡。遗传分析表明，冈比亚按蚊的基因变异与蚊子中疟原虫卵囊的数量有关。识别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。以这些基因为靶点将导致控制寄生虫传播的新方法。然而，使用传统方法很难确定蚊子基因组中约3亿个碱基对和约1.5万个基因的致病突变。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有关的基因。本研究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。肯尼亚西部冈比亚种群和恶性疟原虫寄生虫。将系统地进行直接关联研究，以检测与非洲冈比亚按蚊野生种群的恶性疟原虫感染强度有关的遗传变异。然后，将在实验室条件下和非洲的野外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探讨。计算方法、实验室中的分子功能分析和实地昆虫学研究的组合是解决昆虫-寄生虫相互作用的一套非常强大的工具。这个职业项目将整合从K-12到研究生的研究和教育，无论是当地的、国家的还是国际的。K-12的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和寄生虫相互作用的研讨会。还将在肯尼亚恶性疟原虫感染流行的社区举办教育研讨会。虽然本科生和研究生在研究中发挥了重要作用，但研究计划也为课堂教育提供了材料和资源。最终，将建立一个出色的研究计划和一门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.