Potential involvement of Brugia malayi cysteine proteases in the maintenance of the endosymbiotic relationship with Wolbachia.
Potential involvement of Brugia malayi cysteine proteases in the maintenance of the endosymbiotic relationship with Wolbachia.
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DOI：
10.1016/j.ijpddr.2014.08.001
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发表时间：
2014-12
影响因子：
4
通讯作者：
Ghedin, Elodie
中科院分区：
文献类型：
--
作者：
Lustigman, Sara;Melnikow, Elena;Anand, Setty Balakrishnan;Contreras, Aroha;Nandi, Vijay;Liu, Jing;Bell, Aaron;Unnasch, Thomas R.;Rogers, Mathew B.;Ghedin, Elodie
Bm-cpl-3和Bm-cpl-6参与了发育和内共生过程。在四环素处理的蠕虫中，bm - cp3和-6以双峰模式调节。Bm-cpl-3和-6水平的降低导致微丝虫发育受阻。Bm-cpl-3和-6水平降低导致沃尔巴克氏体DNA水平降低。这些酶可能是强有力的药物候选靶点。马来布鲁贾线虫是一种引起淋巴丝虫病的寄生线虫，它含有细胞内共生细菌沃尔巴克氏体，这是蠕虫发育和繁殖所必需的。这种内共生的本质导致了抗沃尔巴克氏体化疗方法的发展，用于治疗人类丝虫病感染。我们的研究旨在鉴定在这种内共生关系中起关键作用的特定蛋白质，从而鉴定成虫的潜在靶标。已知丝虫半胱氨酸蛋白酶参与蜕皮和胚胎发生，这一过程也被证明是沃尔巴克氏体依赖的。基于观察到半胱氨酸蛋白酶转录物在响应四环素治疗时受到不同的调节，我们重点研究了它们在共生中的作用。我们观察到编码半胱氨酸蛋白酶的转录本的双峰调节模式，当体外四环素处理的蠕虫被检查。利用四环素处理的不育雌虫和纯化的胚胎，我们确定了双峰模式的第一个峰对应于胚胎转录本，而第二个峰发生在成虫的皮下。对Bm-cpl-3和Bm-cpl-6对应的天然蛋白的定位研究表明，它们存在于沃尔巴克氏体周围的区域，在某些情况下，这些蛋白似乎定位在细菌内部。这两种蛋白也在微丝虫的体内被发现。这些半胱氨酸蛋白酶在发育和内共生过程中的可能作用通过RNAi进一步表征。Bm-cpl-3和Bm-cpl-6转录物水平的降低伴随着微丝虫发育和释放的阻碍，以及沃尔巴克氏体DNA水平的降低，使这些酶成为强有力的药物候选靶点。
Bm-cpl-3 and Bm-cpl-6 are involved during development and endosymbiosis. In tetracycline-treated worms Bm-cpl-3 and -6 are regulated in a bimodal pattern. Reduction in Bm-cpl-3 and -6 levels resulted in hindered microfilarial development. Reduction in Bm-cpl-3 and -6 levels resulted in reduced Wolbachia DNA levels. These enzymes might be strong drug target candidates. Brugia malayi, a parasitic nematode that causes lymphatic filariasis, harbors endosymbiotic intracellular bacteria, Wolbachia, that are required for the development and reproduction of the worm. The essential nature of this endosymbiosis led to the development of anti-Wolbachia chemotherapeutic approaches for the treatment of human filarial infections. Our study is aimed at identifying specific proteins that play a critical role in this endosymbiotic relationship leading to the identification of potential targets in the adult worms. Filarial cysteine proteases are known to be involved in molting and embryogenesis, processes shown to also be Wolbachia dependent. Based on the observation that cysteine protease transcripts are differentially regulated in response to tetracycline treatment, we focused on defining their role in symbiosis. We observe a bimodal regulation pattern of transcripts encoding cysteine proteases when in vitro tetracycline treated worms were examined. Using tetracycline-treated infertile female worms and purified embryos we established that the first peak of the bimodal pattern corresponds to embryonic transcripts while the second takes place within the hypodermis of the adult worms. Localization studies of the native proteins corresponding to Bm-cpl-3 and Bm-cpl-6 indicate that they are present in the area surrounding Wolbachia, and, in some cases, the proteins appear localized within the bacteria. Both proteins were also found in the inner bodies of microfilariae. The possible role of these cysteine proteases during development and endosymbiosis was further characterized using RNAi. Reduction in Bm-cpl-3 and Bm-cpl-6 transcript levels was accompanied by hindered microfilarial development and release, and reduced Wolbachia DNA levels, making these enzymes strong drug target candidates.
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影响因子：
30.8
作者：
Desjardins, Christopher A.;Cerqueira, Gustavo C.;Goldberg, Jonathan M.;Hotopp, Julie C. Dunning;Haas, Brian J.;Zucker, Jeremy;Ribeiro, Jose M. C.;Saif, Sakina;Levin, Joshua Z.;Fan, Lin;Zeng, Qiandong;Russ, Carsten;Wortman, Jennifer R.;Fink, Doran L.;Birren, Bruce W.;Nutman, Thomas B.
通讯作者：
Nutman, Thomas B.
影响因子：
4.8
作者：
Lustigman, S;McKerrow, JH;Brotman, B
通讯作者：
Brotman, B
影响因子：
4
作者：
Arumugam, Sridhar;Pfarr, Kenneth M.;Hoerauf, Achim
通讯作者：
Hoerauf, Achim
影响因子：
56.9
作者：
Ghedin, Elodie;Wang, Shiliang;Scott, Alan L.
通讯作者：
Scott, Alan L.
影响因子：
1.5
作者：
Lustigmana, S;Zhang, J;Hashmi, S
通讯作者：
Hashmi, S