Host Defense in Oral Candidiasis

口腔念珠菌病的宿主防御

基本信息

批准号：
7848268
负责人：
Amy G Hise
金额：
$ 34.46万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-06-22 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7848268
关键词：
Accounting Acquired Immunodeficiency Syndrome Acute Adult Age Antifungal Agents Binding Candida Candida albicans Caspase-1 Cells Complex Disease Down-Regulation Drug resistance Epithelial Epithelial Cells Equilibrium Family Genetic Transcription Germ Lines Goals Growth Highly Active Antiretroviral Therapy Host Defense Human Immune Immune response Immunologic Receptors In Vitro Infant Infection Inflammatory Inflammatory Response Interleukin-1 Interleukin-1 Receptors Ligands Mediating Membrane Microbe Modality Modeling Molecular Molecular Structure Mus Neonatal Oral Oral candidiasis Oral cavity Oral mucous membrane structure Pain Pathogenesis Pathway interactions Pattern Pattern recognition receptor Predisposition Prevalence Process Production Research Personnel Risk Role Signal Transduction Pathway Signaling Molecule System TLR1 gene TLR2 gene TLR4 gene Testing Therapeutic Tissues Toll-like receptors Transcriptional Regulation age related chemotherapy cytokine dectin 1 immunoregulation in vivo mouse model neonate novel strategies oral bacteria oral cavity epithelium oral pathogen oropharyngeal thrush pathogen procaspase-1 programs receptor receptor expression research study response

Accounting Acquired Immunodeficiency Syndrome Acute Adult Age Antifungal Agents Binding Candida Candida albicans Caspase-1 Cells Complex Disease Down-Regulation Drug resistance Epithelial Epithelial Cells Equilibrium Family Genetic Transcription Germ Lines Goals Growth Highly Active Antiretroviral Therapy Host Defense Human Immune Immune response Immunologic Receptors In Vitro Infant Infection Inflammatory Inflammatory Response Interleukin-1 Interleukin-1 Receptors Ligands Mediating Membrane Microbe Modality Modeling Molecular Molecular Structure Mus Neonatal Oral Oral candidiasis Oral cavity Oral mucous membrane structure Pain Pathogenesis Pathway interactions Pattern Pattern recognition receptor Predisposition Prevalence Process Production Research Personnel Risk Role Signal Transduction Pathway Signaling Molecule System TLR1 gene TLR2 gene TLR4 gene Testing Therapeutic Tissues Toll-like receptors Transcriptional Regulation age related chemotherapy cytokine dectin 1 immunoregulation in vivo mouse model neonate novel strategies oral bacteria oral cavity epithelium oral pathogen oropharyngeal thrush pathogen procaspase-1 programs receptor receptor expression research study response

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项目摘要

DESCRIPTION (provided by applicant): Perturbations in host defenses can result in overgrowth of pathogens such as Candida albicans, resulting in a painful and debilitating condition, oropharyngeal candidiasis (OPC). Inadequate immune responses, through aging, chemotherapy or immune deficiency, are associated with increased risk of OPC. These disorders are reemerging due to the prevalence of AIDS, both in the underdeveloped world where HAART is not available, and in cases where drug resistance develops. The proinflammatory cytokine, interleukin-1 is critical in host defense against both disseminated and mucosal Candida infections yet the mechanisms that underlie the production of IL-1 or of IL-1-mediated protection in OPC are unknown. We have developed a mouse model of OPC that will be utilized to determine the innate immune mechanisms regulating IL-1 (3 production in vivo and will develop in vitro systems to define these mechanisms in molecular detail. Acute inflammatory responses are generated via germ-line encoded pattern-recognition receptors (PRRs) that recognize specific molecular structures on pathogens known as pathogen associated molecular patterns (PAMPs). Toll-like receptors (TLRs) constitute a class of membrane bound PRRs expressed on host cells, including human oral epithelial cells (HOECs). In addition to TLRs, a large family of cytoplasmic PRRs known as the NACHT-LRRs (NLRs) or inflammasome have been implicated in innate responses, particularly in the processing of the immature form of IL-1 (pro-IL-1). The central hypothesis to be tested is that interactions of fungal pathogens with TLRs (with or without the TLR2 co-receptor, dectin-1) or NLRs at the oral mucosa are critical for controlling Candida infections in the oral cavity and that induction of IL-1P is critical for protection. We propose the following specific aims: 1) To identify critical PRRs involved in the pathogenesis of localized and disseminated infection in OPC, 2) To define the potential role of the NLR family in the induction, processing and release of IL-1P in Candida infections. The ontogeny of expression and function of these innate PRRs will be defined. The long term goals of this project are to determine the innate immune receptors and pathways involved in host defense against the oral pathogen Candida albicans and develop novel approaches to host immunomodulation and anti-fungal therapeutic modalities.

描述（由申请人提供）：宿主防御的扰动会导致白色念珠菌等病原体过度生长，从而导致痛苦而令人衰弱的状况，口咽念珠菌病（OPC）。通过衰老，化学疗法或免疫缺乏，免疫反应不足与OPC风险增加有关。由于艾滋病的流行，这些疾病正在重新出现，既在没有可用的HAART的欠发达世界中，并且在耐药性发展的情况下。促炎性细胞因子白介素-1对于宿主防御抗体和粘膜念珠菌感染至关重要，但尚不清楚IL-1或IL-1介导的保护的基础的机制尚不清楚。 We have developed a mouse model of OPC that will be utilized to determine the innate immune mechanisms regulating IL-1 (3 production in vivo and will develop in vitro systems to define these mechanisms in molecular detail. Acute inflammatory responses are generated via germ-line encoded pattern-recognition receptors (PRRs) that recognize specific molecular structures on pathogens known as pathogen associated molecular patterns (PAMPs). Toll样受体（TLR）构成一类膜结合的PRR，包括人类口腔上皮细胞（HOEC），除了TLR，一个大的细胞质家族称为NACHT-LRRS（NLRS）（NLRS）或炎症，尤其是在原始响应中，尤其是对nacht-lrrs（NLRS）或炎症。要测试的中心假设是，在口腔粘膜上，真菌病原体与TLR（有或没有TLR2共受体，dectin-1）或NLR的相互作用对于控制口腔腔中的念珠菌感染至关重要，并且对IL-1P的诱导至关重要。我们提出以下具体目的：1）确定与OPC中局部和传播感染的发病机理有关的关键PRR，2）确定NLR家族在念珠菌感染中IL-1P的诱导，处理和释放中的潜在作用。将定义这些先天PRR的表达和功能的个体发育。该项目的长期目标是确定针对口腔病原体白色念珠菌的宿主防御涉及的先天免疫受体和途径，并开发新的方法来宿主免疫调节和抗真菌治疗方式。