Figure 1.

Molecular events characteristic of interactions of fungi with mucosal surfaces. Fungi including C. albicans colonize healthy human skin and other mucosal surfaces in yeast form. In healthy individuals, yeast colonization does not induce epithelial damage or an intense cytokine response. During infection or dysbiosis in the context of diseases, yeast transform into hyphal form, gaining access to underlying host tissues (albeit hyphal transition does not occur in certain species including C. glabrata). Fungal components such as mannans, mannoproteins, β-glucans, and chitin are sensed by innate antigen-presenting cells through pattern-recognition receptors (PRRs) on their surface. Dectin-1 activation and the phosphorylation of the receptor at the cytoplasmic domain leads to the activation of spleen tyrosine kinase (Syk). Upon activation, a series of events leads to the assembly of a complex that activates the NF-kB pathway. NF-kB activation results in the release of pro-inflammatory cytokines and reactive oxygen species (ROS) triggering phagocytosis. These events also lead to inflammasome activation, triggering IL-1β and IL-18 production that further prime the innate immune activation. Some of the cytokines modulate PI3K/AKT and glycolytic pathways, instructing T-helper (Th)1, Th17, and regulatory T-cell (T_reg) polarization and their functions. Th17 cells additionally promote the production of innate anti-microbial proteins. For example, pro-inflammatory cytokines secreted by macrophages induce a Th17 response releasing IL-22, which stimulates defensin secretion by epithelial cells. Besides the activation of the immune system, direct production of acetaldehyde resulting from Candida metabolism inhibits the expression of glucose transporter1 (GLUT1) and hypoxia-inducible factor-1α (HIF-1α), which subsequently may also control Th and T_reg homeostasis. Thus, fungal dysbiosis modulates local immune milieu and alters Th functions, which significantly switches the balance between health and disease states.