Regulation of innate responses during pre-patent schistosome infection provides an immune environment permissive for parasite development.
Regulation of innate responses during pre-patent schistosome infection provides an immune environment permissive for parasite development.
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潜伏期血吸虫感染过程中对先天反应的调节为寄生虫的发育提供了一个允许的免疫环境。
DOI：
10.1371/journal.ppat.1003708
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发表时间：
2013
期刊：
影响因子：
6.7
通讯作者：
Davies SJ
中科院分区：
文献类型：
--
作者：
Riner DK;Ferragine CE;Maynard SK;Davies SJ
血吸虫属的血吸虫感染超过 2 亿人，引起肉芽肿病理并伴随发病和死亡。由于广泛的宿主-寄生虫共同进化，血吸虫与宿主表现出复杂的关系，其中免疫因素与寄生虫的发育密切相关。血吸虫在免疫缺陷小鼠中无法正常发育，这一结果特别依赖于 CD4+ T 细胞的缺乏。 CD4+ T 细胞在寄生虫发育中的作用是间接的，并通过与先天细胞的相互作用介导，因为在缺乏 CD4+ T 细胞的情况下，重复 Toll 样受体 4 刺激足以恢复免疫缺陷小鼠的寄生虫发育。在这里，我们表明，通过内源性危险信号反复刺激先天免疫也可以恢复寄生虫的发育，并且这两种刺激在重复施用时会导致先天反应的调节。我们证明，通过中和抗 TNF 抗体来调节炎症也能恢复免疫缺陷小鼠的寄生虫发育，这支持了先天反应调节在寄生虫发育中的作用。最后，我们证明给免疫缺陷小鼠施用 IL-4 通过诱导 2 型反应来调节炎症也能恢复寄生虫的发育。这些发现表明，在免疫活性宿主的专利前感染过程中，CD4+ T 细胞驱动的 2 型反应被血吸虫利用，以完成其向生殖成熟的成虫寄生虫的发育。血吸虫病是一种由血吸虫血吸虫引起的毁灭性疾病，是发展中国家发病率和死亡率的主要原因。对组织中血吸虫卵的炎症反应的调节对于宿主的生存至关重要，并且在卵沉积开始之前就已建立，细胞因子 IL-4 的产生是这一过程的标志。在这里，我们表明炎症反应的调节也有助于血吸虫发育成产卵成虫。我们证明，免疫缺陷小鼠中血吸虫发育失败与受感染的野生型小鼠中缺乏慢性肝脏炎症和随后的免疫调节有关。通过重复给予肝毒素来恢复免疫缺陷小鼠的肝脏炎症，从而恢复寄生虫的发育。重复施用内源性炎症刺激物也恢复了寄生虫的发育，并且还恢复了野生型小鼠中发现的免疫调节的各个方面。最后，对免疫缺陷动物单独施用 IL-4 也能恢复寄生虫的发育和炎症的调节。我们认为血吸虫需要炎症的免疫调节才能在宿主体内的敌对免疫环境中发展。因此，靶向调节炎症可能代表一种治疗或预防血吸虫感染的新方法。
Blood flukes of the genus Schistosoma infect over 200 million people, causing granulomatous pathology with accompanying morbidity and mortality. As a consequence of extensive host-parasite co-evolution, schistosomes exhibit a complex relationship with their hosts, in which immunological factors are intimately linked with parasite development. Schistosomes fail to develop normally in immunodeficient mice, an outcome specifically dependent on the absence of CD4+ T cells. The role of CD4+ T cells in parasite development is indirect and mediated by interaction with innate cells, as repeated toll-like receptor 4 stimulation is sufficient to restore parasite development in immunodeficient mice in the absence of CD4+ T cells. Here we show that repeated stimulation of innate immunity by an endogenous danger signal can also restore parasite development and that both these stimuli, when administered repeatedly, lead to the regulation of innate responses. Supporting a role for regulation of innate responses in parasite development, we show that regulation of inflammation by neutralizing anti-TNF antibodies also restores parasite development in immunodeficient mice. Finally, we show that administration of IL-4 to immunodeficient mice to regulate inflammation by induction of type 2 responses also restores parasite development. These findings suggest that the type 2 response driven by CD4+ T cells during pre-patent infection of immunocompetent hosts is exploited by schistosomes to complete their development to reproductively mature adult parasites. Schistosomiasis is a devastating disease caused by Schistosoma blood flukes and is a leading parasitic cause of morbidity and mortality in the Developing World. The regulation of inflammatory responses to schistosome eggs trapped in tissues is critical for host survival and is established before egg deposition begins, with the production of the cytokine IL-4 being a hallmark of this process. Here we show that regulation of inflammatory responses also contributes to the development of schistosomes into egg-laying adult parasites. We demonstrate that failure of schistosome development in immunodeficient mice correlates with the absence of the chronic liver inflammation and subsequent immune regulation found in infected wild type mice. Restoration of liver inflammation in immunodeficient mice by repeated administration of liver toxins restored parasite development. Repeated administration of an endogenous inflammatory stimulus also restored parasite development, and also restored aspects of the immune regulation found in wild type mice. Finally, administration of IL-4 alone to immunodeficient animals also restored parasite development and the regulation of inflammation. We propose that schistosomes require immune regulation of inflammation to develop in the hostile immune environment within their hosts. Hence, targeting regulation of inflammation may represent a novel approach to treating or preventing schistosome infections.
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影响因子：
82.9
作者：
通讯作者：
--
影响因子：
64.8
作者：
Alexopoulou, L;Holt, AC;Flavell, RA
通讯作者：
Flavell, RA
影响因子：
56.9
作者：
Davies, SJ;Grogan, JL;McKerrow, JH
通讯作者：
McKerrow, JH
DOI：
10.1126/science.1168988
发表时间：
2009-03-27
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Chen GY;Tang J;Zheng P;Liu Y
通讯作者：
Liu Y
影响因子：
4.4
作者：
Fallon, PG;Richardson, EJ;McKenzie, ANJ
通讯作者：
McKenzie, ANJ