Oral commensal fungi and structural immunity

项目总结 虽然真菌白色念珠菌在很大程度上被研究为病原体，但它的主要生活方式是 在包括口腔在内的粘膜表面共生。占据粘膜表面的微生物有 对于适当调整免疫反应以确保对入侵病原体的有效反应至关重要，同时 限制针对宿主组织的反应。在这种背景下，共生真菌在寄主中扮演着重要的角色 免疫和炎症。例如，白念珠菌的定植诱导T细胞和先天T细胞的交叉反应 免疫细胞中的记忆，一种被称为训练免疫的机制。从我们组收集证据和 其他人已经令人信服地证明，口腔与白色念珠菌的共生导致特定的 免疫反应，因此有助于粘膜免疫系统的可塑性。然而，最根本的是 口腔白念珠菌定植的免疫学后果仍不清楚。宿主组织维持 微生物接触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变化。“结构免疫”，免疫 由结构细胞(如内皮细胞和上皮细胞)创建的组织框架内的反应是 对维持耐受性和发展适当的保护性和可控性免疫至关重要 回应。在探索维持口腔有效粘膜免疫的结构过程中，我们 确定了口腔共生白色念珠菌定植过程中调整的两种机制，口腔上皮 增殖和血管生成。我们的中心假设是口腔中的共生白色念珠菌 通过诱导口腔上皮训练免疫、上皮重塑和 血管生成。这些组织重塑和先天启动事件有助于维持有效的粘膜免疫， 从而防止这种重要共生生物体的口腔真菌生长。这项提案将评估 口腔共生白色念珠菌诱导上皮细胞增殖的分子机制(目标1)，以及 血管生成(Aim1和Aim2)。在Aim1中，我们将描述IL-22在介导口腔结构性免疫中的作用。 对共生白色念珠菌定植的反应。在目标2中，我们将确定血管内皮生长因子作为血管内皮生长因子的介体的作用。 口腔内的训练有素和结构性免疫。

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.