Reduction of disulphide bonds unmasks potent antimicrobial activity of human β-defensin 1
Reduction of disulphide bonds unmasks potent antimicrobial activity of human β-defensin 1
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DOI：
10.1038/nature09674
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发表时间：
2011-01-20
期刊：
影响因子：
64.8
通讯作者：
Wehkamp, Jan
中科院分区：
文献类型：
--
作者：
Schroeder, Bjoern O.;Wu, Zhihong;Wehkamp, Jan
人类上皮细胞受到细菌和真菌的永久挑战，包括共生和致病微生物区系(1，2)。在肠道中，严格厌氧菌的比例从近端到远端增加，达到结肠中99%的细菌种类(3)。在结肠粘膜，氧分压低于空气中氧含量的25%，而且微生物代谢导致结肠的氧化还原电位降低到-200 mV到-300 mV(4)。防御素以分子内三个二硫键为特征，是天然免疫的关键效应分子，保护宿主免受感染微生物的侵袭，并塑造粘膜表面微生物群的组成(5-8)。人β-防御素1(hBD-1)是其最重要的多肽之一，但尽管在所有人的上皮细胞中都有表达，但与其他防御素相比，只有轻微的抗生素杀伤活性(9，10)。虽然关于抗菌肽在有氧环境中的活性已知很多，但关于还原环境的数据有限。在这里，我们表明，在减少二硫键后，HBD-1成为一种有效的抗菌肽，可以对抗条件致病真菌白色念珠菌以及双歧杆菌和乳杆菌的厌氧、革兰氏阳性共生菌。还原的HBD-1在结构上不同于氧化的HBD-1，羧基上的游离半胱氨酸似乎对杀菌作用很重要。在体外，硫氧还蛋白(TRX)系统(11)能够减少HBD-1，并且TRX与减少的HBD-1在人的上皮细胞中共定位。因此，我们的研究表明，减少的HBD-1保护健康的上皮免受共生细菌和机会性真菌的侵袭。因此，氧化还原调节和先天免疫防御之间的密切相互作用似乎对保护人类上皮细胞的有效屏障至关重要。
Human epithelia are permanently challenged by bacteria and fungi, including commensal and pathogenic microbiota(1,2). In the gut, the fraction of strict anaerobes increases from proximal to distal, reaching 99% of bacterial species in the colon(3). At colonic mucosa, oxygen partial pressure is below 25% of airborne oxygen content, moreover microbial metabolism causes reduction to a low redox potential of -200 mV to -300 mV in the colon(4). Defensins, characterized by three intramolecular disulphide-bridges, are key effector molecules of innate immunity that protect the host from infectious microbes and shape the composition of microbiota at mucosal surfaces(5-8). Human beta-defensin 1 (hBD-1) is one of the most prominent peptides of its class but despite ubiquitous expression by all human epithelia, comparison with other defensins suggested only minor antibiotic killing activity(9,10). Whereas much is known about the activity of antimicrobial peptides in aerobic environments, data about reducing environments are limited. Herein we show that after reduction of disulphide-bridges hBD-1 becomes a potent antimicrobial peptide against the opportunistic pathogenic fungus Candida albicans and against anaerobic, Gram-positive commensals of Bifidobacterium and Lactobacillus species. Reduced hBD-1 differs structurally from oxidized hBD-1 and free cysteines in the carboxy terminus seem important for the bactericidal effect. In vitro, the thioredoxin (TRX) system(11) is able to reduce hBD-1 and TRX co-localizes with reduced hBD-1 in human epithelia. Hence our study indicates that reduced hBD-1 shields the healthy epithelium against colonisation by commensal bacteria and opportunistic fungi. Accordingly, an intimate interplay between redox-regulation and innate immune defence seems crucial for an effective barrier protecting human epithelia.