Functional and phylogenetic characterization of vaginolysin, the human-specific cytolysin from Gardnerella vaginafis
Functional and phylogenetic characterization of vaginolysin, the human-specific cytolysin from Gardnerella vaginafis
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DOI：
10.1128/jb.01965-07
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发表时间：
2008-06-01
影响因子：
3.2
通讯作者：
Ratner, Adam J.
中科院分区：
文献类型：
--
作者：
Gelber, Shari E.;Aguilar, Jorge L.;Ratner, Adam J.
孔形成毒素是多种病原菌毒力的关键。阴道加德纳菌是一种与细菌性阴道病（BV）及其严重不良后遗症（包括早产和获得人类免疫缺陷病毒）相关的细菌。G.迷走神经炎产生宿主免疫应答的蛋白质毒素，并被假设参与BV的发病机制。我们证明了G.阴道炎产生一种毒素（阴道溶素[VLY]），该毒素是胆固醇依赖性细胞溶素（CDC）家族的成员，与来自中间链球菌的中间溶素最密切相关。与这种预测的关系一致，VLY以物种特异性方式裂解靶细胞，依赖于补体调节分子CD 59。除了引起红细胞溶解外，VLY还激活保守的上皮p38有丝分裂原活化蛋白激酶途径并诱导人上皮细胞产生白细胞介素-8。将人CD 59转染到非易感细胞中使其对VLY介导的裂解敏感。此外，VLY十一肽[VLY（P480 W）]中的单个氨基酸取代产生不形成孔的类毒素，并且将类似的脯氨酸残基引入另一种CDC（肺炎球菌溶血素）中显著降低其细胞溶解活性。对VLY作用机制的进一步研究将有助于加深对CDC家族功能的理解，并有助于BV的诊断和治疗。
Pore-forming toxins are essential to the virulence of a wide variety of pathogenic bacteria. Gardnerella vaginalis is a bacterial species associated with bacterial vaginosis (BV) and its significant adverse sequelae, including preterm birth and acquisition of human immunodeficiency virus. G. vaginalis makes a protein toxin that generates host immune responses and has been hypothesized to be involved in the pathogenesis of BV. We demonstrate that G. vaginalis produces a toxin (vaginolysin [VLY]) that is a member of the cholesterol-dependent cytolysin (CDC) family, most closely related to intermedilysin from Streptococcus intermedius. Consistent with this predicted relationship, VLY lyses target cells in a species-specific manner, dependent upon the complement regulatory molecule CD59. In addition to causing erythrocyte lysis, VLY activates the conserved epithelial p38 mitogen-activated protein kinase pathway and induces interleukin-8 production by human epithelial cells. Transfection of human CD59 into nonsusceptible cells renders them sensitive to VLY-mediated lysis. In addition, a single amino acid substitution in the VLY undecapeptide [VLY(P480W)] generates a toxoid that does not form pores, and introduction of the analogous proline residue into another CDC, pneumolysin, significantly decreases its cytolytic activity. Further investigation of the mechanism of action of VLY may improve understanding of the functions of the CDC family as well as diagnosis and therapy for BV.