Host-pathogen interactions in filarial worm infections

沃尔巴克氏菌是节肢动物和丝虫中常见的胞内细菌。丝虫与它们的互惠共生体和强制性内共生体之间的联系与沃尔巴克氏菌与昆虫之间的联系不同：在蠕虫中，它们似乎为适应和生存提供了关键因素，而昆虫在没有沃尔巴克氏菌的情况下大多是可以生存的。该项目评估了沃尔巴克氏菌如何影响宿主基因的调节，它们如何获得生存所必需的代谢物，以及它们如何逃避宿主的细胞内免疫防御。在这个项目中，我们正在评估沃尔巴克氏杆菌如何改变它们感染的宿主细胞的转录图谱。我们已经在马来丝虫中发现了对沃尔巴克氏菌干扰有差异调控的miRNAs，我们正在测试在有或没有沃尔巴克氏菌的蚊子细胞系中差异表达的miRNAs。我们的目标是通过miRNA操作来表征受Wolbachia调控的宿主基因。我们还在研究细胞自噬的诱导，这被证明可以大幅减少蠕虫中的细菌数量，并阻止胚胎发生和处理后的雌虫释放微丝虫(MF)。我们已经确定了诱导线虫自噬的化合物，并计划测试它们在成虫中消除沃尔巴克氏菌的能力。我们的研究结果可能有助于指导未来对一组确定的马来芽胞杆菌基因的研究，这些基因对维持沃尔巴克氏丝虫和丝虫的相互依存关系非常重要，并有助于寻找影响共生的新型大丝虫杀菌药物。

Wolbachia are common intracellular bacteria found in arthropods and filarial nematodes. The association between filarial worms and their mutualistic and obligatory endosymbionts is different from that of Wolbachia with insects: in worms they appear to provide crucial elements for fitness and survival, whereas the insects are mostly viable without Wolbachia. This project evaluates how Wolbachia impact the regulation of host genes, how they obtain essential metabolites for their survival, and how they evade the hosts intracellular immune defenses. In this project we are evaluating how Wolbachia change the transcriptional profile of the host cells they infect. We have identified miRNAs that are differentially regulated in response to Wolbachia disruption in B. malayi worms, and we are testing miRNAs identified as differentially expressed in mosquito cell lines with or without Wolbachia. We aim to characterize host genes that are regulated by Wolbachia via miRNA manipulation. We are also looking at the induction of cellular autophagy which was shown to drastically decrease the number of bacteria in worms, and to block embryogenesis and the release of microfilariae (Mf) by treated female worms. We have identified chemical compounds that induce autophagy in nematodes, and plan to test their ability to eliminate Wolbachia in adult worms. The results from our research could help direct future investigations into a defined set of B. malayi genes that are important for maintaining the Wolbachia-filarial worm mutualistic co-dependencies, and aid in the search for novel macrofilaricidal drugs that affect symbiosis.