Host Defense in Oral Candidiasis

口腔念珠菌病的宿主防御

• 批准号: 7840840
• 负责人: Amy G Hise
• 金额: $ 1.57万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-16 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7840840
• 关键词: Accounting; Acquired Immunodeficiency Syndrome; Acute; Adult; Age; Aging; 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

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-1or 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 systemsto 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.

在宿主防御的扰动可导致病原体的过度生长，如白色念珠菌，导致