Lower vertebrate immunostimulation and effects on host-pathogen interactions

我的研究计划的长期目标以及这项建议的短期目标是更好地了解鱼类中的寄生虫和其他感染，影响宿主-寄生虫关系的进化驱动因素，鱼类中从杀死到抗原递送的对应对寄生虫感染非常重要的细胞效应器，并开发更好的方法来跟踪/描述具有生态和经济意义的重要鱼类物种的这些机制。加拿大和全球的水产养殖继续扩大，每年生产一半以上的鱼消费，满足对可持续蛋白质来源日益增长的需求。特别是，鲑鱼养殖业在全球范围内是一个每年价值数十亿美元的行业，其中一种寄生虫--鲑鱼(海虱)--的成本/损失估计每年接近10亿美元。基于NSERC先前在我们研究组内的发现和参与资助，我们已经在鲑鱼中鉴定出具有正进化选择压力的性别偏见和毒力因子基因，并通过使用敲除/敲除(KD/KO)-RNAi等技术已经证实它们分别在耐药性(即几丁质结合和ABC G/H转运蛋白基因)和宿主-寄生虫(HP)相互作用(即组织蛋白、下丘脑)中的重要性。由于幽门螺杆菌的相互作用是一种双向关系，我们还发现了在宿主对沙门氏菌和其他寄生虫的反应中重要的先天和适应性标记。值得注意的是，我们观察到鲑鱼中的T细胞群发生了重大变化，虱子感染减少，并发现鲑鱼中的树突状抗原提呈(AP)细胞群对疫苗接种和细胞内寄生虫感染都有反应。这些树突状细胞的增殖与有效的AP和对库多阿百里香的免疫记忆有关，库多阿百里香是一种重要的寄生虫，在许多物种中都会导致软肉综合征，但最引人注目的是不列颠哥伦比亚省养殖的大西洋鲑鱼。因此，我们的目标是(1)研究毒力因子基因与宿主对虱子的免疫反应之间的关系；(2)确定毒力因子KD/KO虱子如何在多代中与野生型虱子竞争，以及它们是否与毒力较低的野生虱子物种有相似之处；(3)鉴定这种新的鲑鱼树突状细胞群，以确定其来源、功能及其在抗寄生虫反应、其他病原体和有效免疫记忆中的重要性。这项研究对于确定环境、免疫和鱼类疾病之间的遗传联系很重要。这些联系应提供有关如何开发更有效的疫苗/免疫刺激干预措施和减少抗生素使用的信息，以提高业界生产更健康和环境可持续的鱼的能力。

The long term goals of my research program, as well as the shorter term objectives of this proposal are to better understand parasitic and other infections in fish, the evolutionary drivers that impact the host-parasite relationship, cellular effectors in fish that are important in response to parasitic infection from killing to antigen presentation, and developing better ways of tracking/characterizing these mechanisms in ecologically and economically important fish species. Aquaculture in Canada, and globally, continues to expand producing over half of the fish consumed on an annual basis and filling the demand for the increasing need of sustainable protein sources. In particular, salmon farming is a multi-billion dollar a year industry globally, in which costs/losses to a single parasite, Lepeophtheirus salmonis (sea lice), are estimated at close to a billion dollars a year. Building upon prior NSERC Discovery and Engage grants within our research group we have identified sex-biased and virulence factor genes in L. salmonis that have positive evolutionary selection pressure, and through the use of knock-down/out (KD/KO)-technologies like RNAi have confirmed their importance in both drug resistance (i.e. chitin binding and ABC G/H transporter genes) and the host-parasite (HP) interaction (i.e cathepsins, hypodermins), respectively. As the HP interaction is a two-sided relationship, we have also identified innate and adaptive markers important in the host response to L. salmonis and other parasites. Of note, we have observed major changes in particular T cell populations in salmon with reduced lice infections and identified dendritic-like antigen presenting (AP) cell populations in salmon to be responsive to both vaccination and intracellular parasitic infection. Proliferation of these dendritic-like cells is related to effective AP and immune memory against Kudoa thyrsites, an important parasite causing soft-flesh syndrome in numerous species, but most notably cultured Atlantic salmon in British Columbia. Therefore our objectives are to (1) investigate the relationship between virulence factor genes and host immune responses to lice, (2) determine how virulence factor KD/KO lice compete with wild-type lice over multiple generations and whether they have similarities to less virulent wild-lice species, and (3) characterize this new dendritic-like cell population of salmon to determine its origins, function, and importance in anti-parasitic responses, other pathogens, and effective immune memory. This research is important for identifying the genetic links between environment, immunity, and disease in fish. These links should provide information on how to develop more effective vaccines/immunostimulatory interventions and reduce antibiotic use, in the interest of enhancing industry's ability to produce a healthier and more environmentally sustainable fish.