Candida albicans-secreted aspartic proteinases modify the epithelial cytokine response in an in vitro model of vaginal candidiasis
Candida albicans-secreted aspartic proteinases modify the epithelial cytokine response in an in vitro model of vaginal candidiasis
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DOI：
10.1128/iai.73.5.2758-2765.2005
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发表时间：
2005-05-01
影响因子：
3.1
通讯作者：
Hube, B
中科院分区：
文献类型：
--
作者：
Schaller, M;Korting, HC;Hube, B
分泌型天冬氨酸蛋白酶(SAPS)是白色念珠菌在黏膜和播散性感染过程中的重要毒力因子，也可能参与诱导炎性宿主免疫反应。我们利用重组人阴道上皮(RHVE)建立阴道念珠菌病模型，研究白色念珠菌对阴道念珠菌病上皮细胞因子的影响。为了研究蛋白水解酶的总活性和不同SAP同工酶的影响，我们研究了蛋白酶抑制剂胃抑素A对免疫应答的影响，并比较了野生型菌株SC5314和SAP缺陷型突变株诱导的细胞因子表达模式。白念珠菌野生型菌株感染RHVE后，与未感染组织中细胞因子的表达相比，可诱导较强的IL-1α、IL-1β、IL-6、IL-8、IL-10、粒细胞-巨噬细胞集落刺激因子、干扰素和肿瘤坏死因子的表达。加入天冬氨酸蛋白酶抑制剂胃抑素A可显著降低RHVE的细胞因子反应。此外，缺乏SAP1或SAP2的SAP缺失突变体可减少组织损伤，并显著降低刺激细胞因子表达的潜力。相反，缺失SAP4到SAP6的突变体的阴道病变和细胞因子诱导能力与野生型相似。这些数据表明，特定分泌物引起组织损伤的可能性与上皮诱导的促炎细胞因子反应有关，这可能是体内控制和管理阴道黏膜白色念珠菌感染的关键。
Secreted aspartyl proteinases (Saps) are important virulence factors of Candida albicans during mucosal and disseminated infections and may also contribute to the induction of an inflammatory host immune response. We used a model of vaginal candidiasis based on reconstituted human vaginal epithelium (RHVE) to study the epithelial cytokine response induced by C. albicans. In order to study the impact of the overall proteolytic activity and of distinct Sap isoenzymes, we studied the effect of the proteinase inhibitor pepstatin A on the immune response and compared the cytokine expression pattern induced by the wild-type strain SC5314 with the pattern induced by Sap-deficient mutants. Infection of RHVE with the C. albicans wild-type strain induced strong interieukin 1 alpha (IL-1 alpha), IL-1 beta, IL-6, IL-8, IL-10, granulocyte-macrophage colony-stimulating factor, gamma interferon, and tumor necrosis factor alpha responses in comparison with cytokine expression in noninfected tissue. Addition of the aspartyl proteinase inhibitor pepstatin A strongly reduced the cytokine response of RHVE. Furthermore, SAP-null mutants lacking either SAP1 or SAP2 caused reduced tissue damage and had a significantly reduced potential to stimulate cytokine expression. In contrast, the vaginopathic and cytokine-inducing potential of mutants lacking SAP4 to SAP6 was similar to that of the wild-type strain. These data show that the potential of specific Saps to cause tissue damage correlates with an epithelium-induced proinflammatory cytokine response, which may be crucial in controlling and managing C. albicans infections at the vaginal mucosa in vivo.