Candida albicans Sap6 Initiates Oral Mucosal Inflammation via the Protease Activated Receptor PAR2.
Candida albicans Sap6 Initiates Oral Mucosal Inflammation via the Protease Activated Receptor PAR2.
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DOI：
10.3389/fimmu.2022.912748
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发表时间：
2022
影响因子：
7.3
通讯作者：
Edgerton, Mira
中科院分区：
文献类型：
--
作者：
Kumar, Rohitashw;Rojas, Isolde Gina;Edgerton, Mira
关键词：
白色念珠菌Sap 6是一种分泌型白念珠菌蛋白酶（Sap），在口腔念珠菌病中起重要作用。除了其蛋白酶活性之外，Sap 6还含有其与宿主整联蛋白结合所需的RGD（RGDRGD）基序。Sap 6激活免疫细胞以诱导促炎细胞因子，尽管其相互作用和激活人口腔上皮细胞（OECs）的能力仍然未知。将纯化的重组Sap 6（rSap 6）加入OECs中导致产生与活菌丝C相似的IL-1β和IL-8细胞因子。白色念珠菌。rSap 6处理的嗅鞘细胞p38和MKP 1磷酸化，c-Fos表达，而C.白色念珠菌Δ sap 6、热灭活的Sap 6或rSap 6 ΔRGD。热灭活的rSap 6能够诱导OECs中的IL-1β而不是IL-8，而rSap 6 ΔRGD诱导IL-8而不是IL-1β，这表明平行的信号传导途径。C.白念珠菌菌丝增加蛋白酶激活受体PAR 1、PAR 2和PAR 3的表面表达，而rSap 6仅增加PAR 2的表达。用PAR 2拮抗剂预处理OECs可阻断rSap 6诱导的p38 MAPK信号传导和IL-8释放，而rSap 6 ΔRGD可独立于PAR 2降低MKP 1信号传导和IL-1β释放。暴露于rSap 6的OECs表现出屏障功能的丧失，如通过TEER测量的，并且E-钙粘蛋白和闭合蛋白连接蛋白水平的降低通过用PAR 2拮抗剂预处理OECs来防止。PAR 2拮抗剂处理的OEC也显示出减少rSap 6介导的C.白色念珠菌细胞因此，Sap 6可以通过PAR 2的蛋白酶激活和其RGD结构域介导启动OEC应答。PAR 2的这种新作用提示了阻断C的新药物靶点。口腔白色念珠菌感染
Candida albicans Sap6, a secreted aspartyl protease (Sap), contributes to fungal virulence in oral candidiasis. Beside its protease activity, Sap6 contains RGD (RGDRGD) motif required for its binding to host integrins. Sap6 activates immune cells to induce proinflammatory cytokines, although its ability to interact and activate human oral epithelial cells (OECs) remain unknown. Addition of purified recombinant Sap6 (rSap6) to OECs resulted in production of IL-1β and IL-8 cytokines similar to live hyphal C. albicans. OECs exposed to rSap6 showed phosphorylation of p38 and MKP1 and expression of c-Fos not found with C. albicans Δsap6, heat-inactivated Sap6, or rSap6ΔRGD . Heat inactivated rSap6 was able to induce IL-1β but not IL-8 in OECs, while rSap6ΔRGD induced IL-8 but not IL-1β suggesting parallel signaling pathways. C. albicans hyphae increased surface expression of Protease Activated Receptors PAR1, PAR2 and PAR3, while rSap6 increased PAR2 expression exclusively. Pretreatment of OECs with a PAR2 antagonist blocked rSap6-induced p38 MAPK signaling and IL-8 release, while rSap6ΔRGD had reduced MKP1 signaling and IL-1β release independent from PAR2. OECs exposed to rSap6 exhibited loss of barrier function as measured by TEER and reduction in levels of E-cadherin and occludin junctional proteins that was prevented by pretreating OECs with a PAR2 antagonist. OECs treated with PAR2 antagonist also showed reduced rSap6-mediated invasion by C. albicans cells. Thus, Sap6 may initiate OEC responses mediated both through protease activation of PAR2 and by its RGD domain. This novel role of PAR2 suggests new drug targets to block C. albicans oral infection.
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