Candida albicans Sap6 dysregulates host epithelial protease-antiprotease expression

白色念珠菌 Sap6 失调宿主上皮蛋白酶-抗蛋白酶表达

基本信息

批准号：
10739848
负责人：
Rohitashw Kumar
金额：
$ 32.15万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10739848
关键词：
Acute Affect Aspartic Endopeptidases Candida Candida albicans Candidiasis Chronic Clinical Treatment Clinical Trials Critical Illness Data Development Disease Disintegrins Epidermal Growth Factor Receptor Epidermis Epithelial Cells Epithelium Extracellular Matrix Family Filament Future Goals Hyphae IL8 gene Immune response Immunocompromised Host Immunologics Impairment In Vitro Infection Inflammation Inflammatory Inflammatory Response Integrins Interleukin-1 beta Invaded Kininogenase Knockout Mice MAP Kinase Gene MMP3 gene MMP9 gene Matrix Metalloproteinase Inhibitor Matrix Metalloproteinases Measures Mediating Metalloproteases Microbe Modeling Morphology Mucous Membrane Mus Mycoses Oral Oral health Outcome Outcome Study Pathogenesis Peptide Hydrolases Permeability Prevention Protease Inhibitor Proteins Public Health Recombinants Research Role Signal Transduction Skin System TIMP2 gene Testing Therapeutic Therapeutic Intervention Tissues Tongue Treatment Cost Virulence Work Yeasts antimicrobial antimicrobial peptide cathelicidin antimicrobial peptide cell motility chemokine chronic inflammatory disease cytokine design fungus healing improved in vivo in vivo Model inhibitor microbial migration mortality new therapeutic target novel therapeutic intervention opportunistic pathogen oral cavity epithelium oral commensal oral pathogen overexpression p38 Mitogen Activated Protein Kinase

项目摘要

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.

白色念珠菌是一种口腔共生酵母，可引起粘膜（口腔或 OPC）和全身（侵入性）感染由于较高的感染率，念珠菌粘膜感染正在成为美国的主要公共卫生威胁。治疗费用和死亡率增加，尤其是免疫功能低下和危重患者。因此，迫切需要改进粘膜白色念珠菌病的预防和治疗。菌丝定殖或侵入口腔上皮细胞，这是物理和免疫防御的第一道防线 C. 白色念珠菌产生分泌型天冬氨酰蛋白酶 (Sap4-6)，通过以下方式对抗上皮免疫反应：用重组 Sap6 蛋白酶处理的 OEC 导致上皮细胞的蛋白水解活性增加。通透性、增加 IL-8、IL-1β 释放、增加上皮迁移和改变宿主蛋白酶水平（激肽释放酶、基质金属蛋白酶和 ADAM）然而，我们不知道 C. 白色念珠菌菌丝和 Sap6 改变 OEC 中的宿主蛋白酶，或者增加哪些蛋白酶是必需的真菌入侵、炎症或 OEC 迁移的变化因此，该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 MMP/ADAM 水平对感染白色念珠菌或 Sap6 的 OEC 迁移的作用。这项工作将确定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子 - 上皮相互作用并确定它们在调节 OEC 中 Sap6 宿主炎症反应中的作用。长期目标是了解白色念珠菌如何利用宿主蛋白酶/抗蛋白酶来诱导急性或这将为识别新的宿主蛋白酶提供急需的基础工作。治疗由口腔微生物引起的急慢性炎症的靶标。