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.

项目摘要 虽然真菌白色念珠菌在很大程度上被作为病原体进行研究，但其主要生活方式是作为一种病原体。 粘膜表面，包括口腔的粘膜。占据粘膜表面的微生物是 对于适当调节免疫应答以确保对入侵病原体的有效应答至关重要， 限制针对宿主组织的反应。在这种背景下，真菌在宿主中起着重要的作用， 免疫和炎症。例如，C.白色念珠菌定植诱导交叉反应性T细胞和先天性 免疫细胞中的记忆，一种称为训练免疫的机制。从我们小组收集证据， 其他人已经令人信服地证明，口部寄生的C.白色念珠菌诱导特异性 免疫反应，因此有助于粘膜免疫系统的可塑性。但根本 口服C.白色念珠菌的定殖仍不清楚。宿主组织维持 微生物相遇后的痕迹或记忆，超出了T和B细胞的适应性反应。这些 变化包括深刻的结构重塑和表观遗传改变。“结构免疫”，免疫 在由结构细胞（例如内皮细胞和上皮细胞）产生的组织框架内的反应， 维持耐受性和发展适当的保护性和控制性免疫至关重要， 应答在探索维持口腔有效粘膜免疫的结构过程中，我们 确定了两种机制，这是调整在口腔颌面部C。白色念珠菌定植，口腔上皮 增殖和血管生成。我们的中心假设是，C.C.口腔内白色念珠菌暴露 通过诱导口腔上皮训练免疫、上皮重塑建立粘膜“结构免疫”， 血管生成这些组织重塑和先天引发事件用于维持有效的粘膜免疫， 从而防止这种重要的口腔微生物的口腔真菌生长。该提案将评估 口腔黏膜上皮细胞C.白色念珠菌诱导上皮细胞增殖（目的1），和 血管生成（Aim 1和2）。在Aim 1中，我们将描述IL-22在介导口腔结构免疫中的作用， 对C的回应白色念珠菌定植。在目标2中，我们将确定VEGF作为介导因子的作用， 口腔中的训练和结构性免疫。