Molecular Parasitology, New York Blood Center, New York, New York, United States of America.
Center for Genomics and Systems Biology, Department of Biology, New York University, New York, New York, United States of America.
PLoS Pathog. 2019 Sep 30;15(9):e1008085. doi: 10.1371/journal.ppat.1008085. eCollection 2019 Sep.
Human parasitic nematodes are the causative agents of lymphatic filariasis (elephantiasis) and onchocerciasis (river blindness), diseases that are endemic to more than 80 countries and that consistently rank in the top ten for the highest number of years lived with disability. These filarial nematodes have evolved an obligate mutualistic association with an intracellular bacterium, Wolbachia, a symbiont that is essential for the successful development, reproduction, and survival of adult filarial worms. Elimination of the bacteria causes adult worms to die, making Wolbachia a primary target for developing new interventional tools to combat filariases. To further explore Wolbachia as a promising indirect macrofilaricidal drug target, the essential cellular processes that define the symbiotic Wolbachia-host interactions need to be identified. Genomic analyses revealed that while filarial nematodes encode all the enzymes necessary for glycolysis, Wolbachia does not encode the genes for three glycolytic enzymes: hexokinase, 6-phosphofructokinase, and pyruvate kinase. These enzymes are necessary for converting glucose into pyruvate. Wolbachia, however, has the full complement of genes required for gluconeogenesis starting with pyruvate, and for energy metabolism via the tricarboxylic acid cycle. Therefore, we hypothesized that Wolbachia might depend on host glycolysis to maintain a mutualistic association with their parasitic host. We did conditional experiments in vitro that confirmed that glycolysis and its end-product, pyruvate, sustain this symbiotic relationship. Analysis of alternative sources of pyruvate within the worm indicated that the filarial lactate dehydrogenase could also regulate the local intracellular concentration of pyruvate in proximity to Wolbachia and thus help control bacterial growth via molecular interactions with the bacteria. Lastly, we have shown that the parasite's pyruvate kinase, the enzyme that performs the last step in glycolysis, could be a potential novel anti-filarial drug target. Establishing that glycolysis is an essential component of symbiosis in filarial worms could have a broader impact on research focused on other intracellular bacteria-host interactions where the role of glycolysis in supporting intracellular survival of bacteria has been reported.
人体寄生线虫是淋巴丝虫病（象皮病）和盘尾丝虫病（河盲症）的病原体，这些疾病流行于 80 多个国家，一直位列导致伤残调整生命年（DALY）最高的十大疾病之列。这些丝虫与一种名为沃尔巴克氏体的细胞内细菌形成了专性共生关系，这种共生体对于成丝虫的成功发育、繁殖和生存是必不可少的。消除这种细菌会导致成虫死亡，因此沃尔巴克氏体成为开发新的干预工具以对抗丝虫病的主要目标。为了进一步探索沃尔巴克氏体作为一种有前途的间接杀微丝蚴药物靶点，需要确定定义共生沃尔巴克氏体-宿主相互作用的必要细胞过程。基因组分析表明，尽管丝虫编码了糖酵解所需的所有酶，但沃尔巴克氏体并不编码三种糖酵解酶的基因：己糖激酶、6-磷酸果糖激酶和丙酮酸激酶。这些酶对于将葡萄糖转化为丙酮酸是必需的。然而，沃尔巴克氏体拥有从丙酮酸开始的完整的糖异生基因，以及通过三羧酸循环进行能量代谢的基因。因此，我们假设沃尔巴克氏体可能依赖宿主糖酵解来维持与寄生宿主的共生关系。我们在体外进行了条件实验，证实了糖酵解及其终产物丙酮酸维持了这种共生关系。对蠕虫中丙酮酸的替代来源的分析表明，丝虫的乳酸脱氢酶也可以调节靠近沃尔巴克氏体的细胞内丙酮酸的局部浓度，并通过与细菌的分子相互作用来帮助控制细菌的生长。最后，我们已经表明，寄生虫的丙酮酸激酶，即糖酵解的最后一步酶，可能是一个潜在的新的抗丝虫药物靶点。确定糖酵解是丝虫共生关系的一个必要组成部分，可能会对专注于其他已报道糖酵解在支持细菌细胞内生存中作用的细胞内细菌-宿主相互作用的研究产生更广泛的影响。
