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

• 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
• 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

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念珠菌，可引起粘膜（口腔或OPC）和全身（侵入性） 感染.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，特别是在免疫功能低下和危重病人中。 因此，迫切需要改进粘膜念珠菌病的预防和治疗。C.白色 菌丝定殖或侵入作为物理和免疫防御的第一道防线的口腔上皮细胞。C. 白色念珠菌产生分泌的乙酰基蛋白酶（Sap 4 -6），其通过以下途径对抗上皮免疫应答： 其蛋白水解活性。用重组Sap 6蛋白酶处理的OEC导致上皮细胞增殖增加， 通透性增加，IL-8、IL-1β释放增加，上皮迁移增加和宿主蛋白酶水平改变 （激肽释放酶、基质金属蛋白酶和亚当斯）。然而，我们不知道C. 白念珠菌菌丝和Sap 6改变OEC中的宿主蛋白酶或增加OEC中的蛋白酶所需的蛋白酶。 真菌入侵、炎症或OEC迁移的变化。因此，本提案的具体目标将 1)确定C.白色念珠菌Sap 6改变OEC激肽释放酶活性和屏障功能，以及2）检查 MMP/ADAM在感染C.白色念珠菌或Sap 6。的预期成果 这项工作将确立宿主激肽释放酶和基质金属蛋白酶作为C.白色念珠菌， 上皮的相互作用，并确定其在调节OEC中对Sap 6的宿主炎症反应中的作用。我们 长期目标是了解C.白色念珠菌利用宿主蛋白酶/抗蛋白酶诱导急性或 慢性免疫反应。这将提供急需的基础工作，以确定新的宿主蛋白酶 用于治疗由口腔微生物引起的急性和慢性炎症的治疗靶标。