Manipulation of stem cell activity and cell death by intracellular bacteria

描述(申请人提供)：由母体传播的细胞内细菌沃尔巴克氏菌的感染在自然界中广泛存在，在大多数昆虫和寄生蠕虫中发现。许多携带这些细菌的昆虫是毁灭性的人类传染病的媒介。沃尔巴克氏菌与寄主交界处的生物学为控制病媒提供了新的策略。果蝇沃尔巴克氏菌株能在蚊子种群中入侵并维持自身，缩短成虫寿命，影响蚊子繁殖，并抑制几种病原体感染蚊子的能力，包括登革热、基孔肯雅、西尼罗河病毒以及鸡疟原虫和人类疟原虫。然而，对沃尔巴克氏菌-昆虫宿主相互作用的机制基础知之甚少，限制了充分利用沃尔巴克氏菌生物学进行控制的能力。这项应用的目的是研究沃尔巴克氏菌操纵昆虫繁殖的细胞和分子机制。沃尔巴克氏菌经常改变宿主的繁殖能力；然而，关于我是如何做到这一点的，我们知之甚少。我们确定了沃尔巴克氏菌干扰提高寄主产卵量水平的发育过程。通过细菌抑制卵子生产过程中生殖细胞的死亡，沃尔巴克氏菌的母体传播得到了加强。此外，沃尔巴克氏杆菌可以上调生殖系干细胞的增殖速度，进一步增加细菌通过TE卵的传播。为了剖析这些新的寄主操作的细胞和分子机制，我们将：1.确定不同的沃尔巴克氏菌株在黑腹蚊虫、淡色库蚊和埃及伊蚊生殖系程序性细胞死亡中的作用。2.研究感染对不同沃尔巴克氏菌株宿主间干细胞分裂的影响。3.确定沃尔巴克氏杆菌引起的影响干细胞增殖的转录图谱的差异。我们在细胞和分子水平上研究Wolbachia与寄主的相互作用，将为卵子发生过程中共生相互作用的基础生物学提供有价值的新信息。这些基础知识为发展新的细胞生物学和基于沃尔巴克氏菌的疾病控制策略奠定了基础。此外，沃尔巴克氏菌与干细胞生态位的相互作用和干细胞增殖的操纵将扩大我们对干细胞生态位的特性及其如何控制干细胞增殖的基本理解。

DESCRIPTION (provided by applicant): Infections of the maternally transmitted intracellular bacteria Wolbachia are widespread in nature, found in most insects and in parasitic worms. Many insects that harbor these bacteria are the vectors of devastating human infectious diseases. The biology at the interface between Wolbachia and their hosts offers novel strategies for the control of disease vectors. Fruit fly Wolbachia strains can invade and sustain themselves in mosquito populations, reduce adult lifespan, affect mosquito reproduction and inhibit the ability of several pathogens to infect mosquitoes, including Dengue, Chikungunya, West Nile Virus, and both chicken and human plasmodium. Nevertheless, very little is known about the mechanistic basis for Wolbachia-insect host interactions, limiting the capability of fully exploitig Wolbachia's biology towards control efforts. The goal of this application is to investigate the cellular and molecular mechanisms of Wolbachia manipulation of insect reproduction. Wolbachia often alter their host's reproductive ability; yet, very little is known about how this i achieved. We identified the developmental processes that Wolbachia interfere with to increase the levels of host egg production. Wolbachia maternal transmission is enhanced by bacterial inhibition of germ cells death during egg production. Furthermore, Wolbachia can upregulate the rate of proliferation of the germline stem cells, further increasing transmission of bacteria via te egg. To dissect the cellular and molecular mechanisms of these novel host manipulations, we will: 1. Determine the effects of different Wolbachia strains in germline programmed cell death in D. melanogaster, Culex pipiens and Aedes aegypti. 2. Investigate the effect of infection on stem cell division with different Wolbachia strain-host species. 3. Determine Wolbachia-induced differences in the transcriptional profile that affect stem cell proliferation. Our studies of Wolbachia interaction with their hosts at the cellular and molecular level will yield valuable new information on basic biology of symbiotic interactions during oogenesis. This fundamental knowledge provide the foundation for the development of new cell biological and Wolbachia based strategies for disease control. Furthermore, Wolbachia interaction with stem cell niches and manipulation of stem cell proliferation will expand our basic understanding of the properties of stem cell niches and how they control stem cell proliferation.