Nitric oxide blocks the development of the human parasite Schistosoma japonicum
Nitric oxide blocks the development of the human parasite Schistosoma japonicum
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一氧化氮阻止人体寄生虫日本血吸虫的发育
DOI：
10.1073/pnas.1708578114
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发表时间：
2017-09-19
影响因子：
11.1
通讯作者：
Lun, Zhao-Rong
中科院分区：
文献类型：
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作者：
Shen, Jia;Lai, De-Hua;Lun, Zhao-Rong
由血吸虫属物种引起的人类血吸虫病是一个重大的公共卫生问题，影响着78个国家的7亿多人，40多种哺乳动物宿主储存宿主物种使传播生态系统变得复杂。发病的主要原因被认为是血吸虫受精卵在肝脏和肠道中诱发的肉芽肿。一些宿主物种，如大鼠（褐家鼠），对日本血吸虫感染具有天然耐受性，不会产生肉芽肿，也不会对传播构成威胁，而其他物种，如小鼠和仓鼠，则高度易感。这些差异背后的原因仍然是个谜。我们利用诱导型一氧化氮合酶基因敲除（iNOS(-/-)）的斯普拉格 - 道利大鼠发现，野生型（WT）大鼠中iNOS的固有高表达水平在阻断日本血吸虫的生长、生殖器官形成和虫卵发育方面起着重要作用，导致产生未受精卵。与野生型大鼠相比，iNOS(-/-)大鼠肝脏中由受精卵诱导的肉芽肿形成明显加剧。一氧化氮的这种抑制作用是通过影响寄生虫的线粒体呼吸和能量产生来实现的。我们的工作不仅阐明了阻断日本血吸虫受精卵发育和产生的先天机制，还为更好地理解宿主 - 寄生虫相互作用以及针对血吸虫病的药物开发策略提供了见解。
Significance Viable egg production by Schistosoma species is the key pathogenic process causing granuloma formation in permissive hosts (e.g., mice), while nonpermissive hosts [e.g., Norway rats (Rattus norvegicus)] avoid such sequelae. Using inducible nitric oxide synthase knockout (iNOS−/−) rats, we demonstrate that high expression levels of iNOS in rats play an important role in blocking the egg-induced granuloma formation of Schistosoma japonicum. The nitric oxide, produced by iNOS, inhibits parasite growth, reproductive organ development, egg production, and viability by interfering with mitochondrial function. This study solves the puzzle as to why rats are naturally resistant to S. japonicum infection and provides insights for understanding the pathogenesis of human schistosomiasis and the interactions between host and parasite. Human schistosomiasis, caused by Schistosoma species, is a major public health problem affecting more than 700 million people in 78 countries, with over 40 mammalian host reservoir species complicating the transmission ecosystem. The primary cause of morbidity is considered to be granulomas induced by fertilized eggs of schistosomes in the liver and intestines. Some host species, like rats (Rattus norvegicus), are naturally intolerant to Schistosoma japonicum infection, and do not produce granulomas or pose a threat to transmission, while others, like mice and hamsters, are highly susceptible. The reasons behind these differences are still a mystery. Using inducible nitric oxide synthase knockout (iNOS−/−) Sprague–Dawley rats, we found that inherent high expression levels of iNOS in wild-type (WT) rats play an important role in blocking growth, reproductive organ formation, and egg development in S. japonicum, resulting in production of nonfertilized eggs. Granuloma formation, induced by fertilized eggs in the liver, was considerably exacerbated in the iNOS−/− rats compared with the WT rats. This inhibition by nitric oxide acts by affecting mitochondrial respiration and energy production in the parasite. Our work not only elucidates the innate mechanism that blocks the development and production of fertilized eggs in S. japonicum but also offers insights into a better understanding of host–parasite interactions and drug development strategies against schistosomiasis.