Oral commensal fungi and structural immunity

口腔共生真菌和结构免疫

• 批准号: 10519004
• 负责人: Marc Swidergall
• 金额: $ 52万
• 依托单位: LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10519004
• 关键词: Acquired Immunodeficiency Syndrome; Acute; Adrenal Cortex Hormones; Antifungal Agents; Antigens; Architecture; B-Lymphocytes; Blood Vessels; Candida; Candida albicans; Cell Proliferation; Cell Wall; Cells; Data; Development; Disease; Elderly; Endothelial Cells; Endothelium; Ensure; Epigenetic Process; Epithelial; Epithelial Cells; Event; Exposure to; Fibroblast Growth Factor; Food; Goals; Human; Immune; Immune response; Immune system; Immunity; Immunologics; Immunosuppression; Immunosuppressive Agents; In Vitro; Individual; Infant; Infection; Inflammation; Inflammatory Response; Inhalation; Integration Host Factors; Invaded; Knowledge; Life Style; Link; Mediating; Mediator of activation protein; Memory; Metabolic; Modeling; Molecular; Mouth Diseases; Mucosal Immune System; Mucosal Immunity; Mucous Membrane; Mus; Mycoses; Oral; Oral candidiasis; Oral cavity; Oral mucous membrane structure; Organism; Pathogenicity; Permeability; Pharmaceutical Preparations; Physiology; Play; Predisposition; Process; Production; Reporter; Research; Role; STAT3 gene; Signal Transduction; Source; Stimulus; Stromal Cells; Surface; T cell response; T-Lymphocyte; Tissues; Training; Transplant Recipients; Vascular Endothelial Cell; acute infection; adaptive immune response; angiogenesis; asthmatic patient; beta-Glucans; chemotherapy; conditional knockout; cross reactivity; cytokine; fungal microbiota; fungus; immune function; interleukin-22; microorganism; mouse model; mucosal vaccine; mycobiome; neutrophil; oral cavity epithelium; oral commensal; oral fungal; oropharyngeal thrush; pathogen; prevent; receptor; recruit; response; vascular contributions

PROJECT SUMMARY While the fungus Candida albicans has largely been studied as a pathogen, its primary lifestyle is as a commensal on mucosal surfaces, including the oral cavity. Microorganisms that occupy mucosal surfaces are critical for appropriately tuning immune responses to ensure efficient responses to invading pathogens while limiting responses directed towards host tissues. In this context, commensal fungi play important roles in host immunity and inflammation. For instance, C. albicans colonization induces cross-reactive T cells and innate memory in immune cells, a mechanism termed trained immunity. Accumulating evidence from our group and others have convincingly demonstrated that oral commensal colonization with C. albicans induces specific immune responses, therefore contributing to mucosal immune system plasticity. However, the fundamental immunological consequences of oral C. albicans colonization are still not well understood. Host tissues maintain traces or memory after microorganism encounter that extend beyond adaptive responses of T and B cells. These changes include profound structural remodeling and epigenetic alterations. ‘Structural immunity’, the immune response within a tissue framework created by structural cells, such as endothelial and epithelial cells, is essential for maintaining tolerance and the development of appropriate protective and controlled immune responses. In probing for structural processes that maintain effective mucosal immunity in the oral cavity, we identified two mechanisms which are tuned during oral commensal C. albicans colonization, oral epithelial proliferation and angiogenesis. Our central hypothesis is that commensal C. albicans exposure in the oral cavity establishes mucosal ‘structural immunity’ by inducing oral epithelial trained immunity, epithelial remodeling, and angiogenesis. These tissue remodeling and innate priming events serve to maintain effective mucosal immunity, thus preventing oral fungal outgrowth of this important commensal organism. This proposal will evaluate the molecular mechanisms by which oral commensal C. albicans induce epithelial proliferation (Aim 1), and angiogenesis (Aim1 and 2). In Aim1 we will delineate the role of IL-22 in mediating oral structural immunity in response to commensal C. albicans colonization. In Aim 2 we will determine the role of VEGF as a mediator of trained and structural immunity in the oral cavity.

项目总结