Candida albicans Sap6 dysregulates host epithelial protease-antiprotease expression

白色念珠菌是一种口腔共生酵母菌，可引起粘膜(口腔或OPC)和全身(侵袭性) 感染。念珠菌黏膜感染正在成为美国主要的公共健康威胁，因为更高的 治疗费用和死亡率增加，特别是在免疫受损和危重病患者中。 因此，迫切需要改进黏膜念珠菌病的预防和治疗。白色念珠菌 菌丝定植或入侵口腔上皮细胞，这是物理和免疫防御的第一道防线。C。 白念珠菌产生分泌型天冬氨酸蛋白酶(SAP4-6)，通过 它们的蛋白质分解活性。重组Sap6蛋白酶诱导嗅鞘细胞上皮细胞增多 通透性增加，IL-8和IL-1β释放增加，上皮迁移增加，宿主蛋白水解酶水平改变 (激肽释放酶、基质金属蛋白酶和亚当斯)。然而，目前尚不清楚C. 白念珠菌菌丝和Sap6改变嗅鞘细胞中的宿主蛋白酶或需要哪些蛋白酶才能增加 真菌侵袭、炎症或嗅鞘细胞迁移改变。因此，这项提案的具体目标将是 1)确定白色念珠菌Sap6如何改变OEC激肽释放酶活性和屏障功能，以及2)检查 基质金属蛋白酶/ADAM在感染白念珠菌或Sap6的嗅鞘细胞迁移中的作用的预期结果 这项工作将建立宿主激肽释放酶和基质金属蛋白酶作为白色念珠菌的重要因素。 在嗅鞘细胞中上皮细胞的相互作用，并确定它们在调节宿主对Sap6的炎症反应中的作用。我们的 长期目标是了解白色念珠菌如何利用宿主蛋白水解酶/抗蛋白水解酶诱导急性或 慢性免疫反应。这将提供急需的基础工作，以确定宿主蛋白酶为新的 治疗口腔微生物引起的急、慢性炎症的治疗靶点。

Candida albicans is an oral commensal yeast that can cause mucosal (oral or OPC) and systemic (invasive) infections. Candida mucosal infections are emerging as major public health threat in the US due to higher treatment costs and increased mortality rates particularly among the immunocompromised and critically ill. Thus, there is an urgent need for improved prevention and treatment of mucosal candidiasis. C. albicans hyphal colonize or invade oral epithelial cells that are the first line of physical and immunological defense. C. albicans produces secreted aspartyl proteases (Sap4-6) that counter epithelial immune responses through their proteolytic activity. OECs treated with recombinant Sap6 protease resulted in increased epithelial permeability, increased IL-8, IL-1β release, increased epithelial migration and altered levels of host proteases (kallikreins, matrix metalloprotease and ADAMs). However, we do not know the mechanism by which C. albicans hyphae and Sap6 change host proteases in OECs or which proteases are required for increased fungal invasion, inflammation or changes in OEC migration. Therefore, the Specific Aims of this proposal will 1) Determine how C. albicans Sap6 modifies OEC Kallikrein activity and barrier function, and 2) Examine the role of MMP/ADAM levels on migration of OECs infected with C. albicans or Sap6. The expected outcomes of this work will establish host Kallikreins and matrix metalloproteases as important factors for C. albicans - epithelial interactions and define their role in modulating host inflammatory responses to Sap6 in OECs. Our long-term goal is to understand how C. albicans exploits host proteases/antiproteases to induce acute or chronic immune responses. This will provide much needed ground work to identify host proteases as new therapeutic targets for treating acute and chronic inflammation caused by oral microbes.