一氧化氮诱导血吸虫内质网应激反应及其机制研究

Schistosomiasis is a serious parasitic disease for public health. Human and most mammals are susceptible to Schistosoma infection, but the rats are exceptions, in which Schistosoma spp. cannot develop well. Therefore, a better understanding of the mechanism of resistance would provide a significant value for academic and application. Using inducible nitric oxide synthase knockout (iNOS−/−) rats, we found that inherent high levels of nitric oxide (NO) in wild-type (WT) rats play an important role in blocking growth and reproductive organ development in Schistosoma japonicum. This inhibition by NO acts by affecting mitochondrial respiration in the parasite. These results have been published in PNAS. Recently, we found that the morphology of endoplasmic reticulum of S. japonicum collected from WT rats showed a notable change, compared with the worms collected from mice and iNOS-/- rats. But the reason is unknown. In this study, with the infected mice, WT rats and iNOS−/− rats, we will compare the differences of endoplasmic reticulum stress of S. japonicum in these hosts, and study the role of endoplasmic reticulum stress in blocking the development of Schistosoma induced by NO. Moreover, we will also study the relationship of endoplasmic reticulum stress and mitochondrial respiration of S. japonicum. The findings from the project would fill in the pathway of NO inhibiting the development of schistosome and further illuminate the mechanism of rats resistant to Schistosoma infection, which would inform potentially novel strategies to design new compounds and drugs to control schistosomiasis.

血吸虫病是严重危害人类健康的寄生虫病。人和大多数哺乳动物对血吸虫易感，而大鼠例外，血吸虫在其体内较难发育成熟。因此，揭示大鼠抗血吸虫感染的机制具有重要的学术和应用价值。利用诱导型一氧化氮合酶基因敲除大鼠（iNOS-/-）模型，我们证实了大鼠体内高水平的一氧化氮（NO）可明显抑制血吸虫的生长发育，其作用机制与虫体线粒体功能受损有关，该研究结果已在PNAS上发表。我们近期研究发现，与小鼠和iNOS-/-大鼠中的血吸虫相比，WT大鼠中的血吸虫内质网发生了明显的变化，但原因不明。本研究拟利用WT、iNOS-/-大鼠及小鼠感染日本血吸虫模型，比较其体内的血吸虫内质网应激的差异，研究NO诱导的血吸虫内质网应激在抑制虫体发育中的作用，探讨血吸虫内质网应激与线粒体功能损伤的关系和机制，进一步完善NO抑制血吸虫发育这一过程的通路，深入阐明大鼠抗血吸虫感染的相关机理，为抗血吸虫的新药开发提供新的思路和靶点。

日本血吸虫病是危害人类健康的重要人畜共患病。人和大多数哺乳动物（包括小鼠）对血吸虫普遍易感，血吸虫在其体内能发育成熟并产生致病性的虫卵。然而，大鼠具有天然抗血吸虫感染的特性，血吸虫在其体内较难发育成熟,不能产生致病性的虫卵。揭示大鼠的这种抗性机制具有重要的学术意义和应用价值。我们前期已证实了大鼠体内高水平的一氧化氮（NO）可明显抑制血吸虫的生长发育，但相关机理还未完全阐明。本项目在3年的执行过程中，按照项目书的研究计划开展。目前完成了① 通过体内和体外实验证实了大鼠体内高水平的NO可诱导日本血吸虫发生内质网应激反应。② 证明了NO诱导日本血吸虫发生的内质网应激反应与虫体发育受阻具有直接的关系，当大鼠体内的日本血吸虫的内质网应激反应被抑制后，其虫体发育及产卵量明显增加。③ 揭示了NO诱导日本血吸虫发生内质网应激反应的机制与内质网腔内Ca2+离子浓度失衡（下降）有关。④证明了日本血吸虫发生内质网应激反应与其线粒体氧化呼吸功能受损具有直接的关系，进一步导致虫体的发育受阻。⑤通过转录组及ATAC测序，提示了NO诱导日本血吸虫发生内质网应激反应的相关分子通路。本研究进一步阐明了大鼠天然抗血吸虫感染的相关机理，为揭示血吸虫的寄生特性提供了新的理论和实验依据。