Division of Infectious Diseases, Center for Inflammation and Tolerance, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA; Immunobiology Graduate Program, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA
Pallavi Kakade
Molecular Microbiology and Immunology Department, Brown University, Providence, RI 02912, USA
Jessica N. Witchley
Department of Microbiology and Immunology, University of California, San Francisco School of Medicine, San Francisco, CA 94143, USA
Corey Frazer
Molecular Microbiology and Immunology Department, Brown University, Providence, RI 02912, USA
Kathryn L. Murray
Division of Infectious Diseases, Center for Inflammation and Tolerance, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA
Iuliana V. Ene
Fungal Heterogeneity Lab, Institut Pasteur, Université Paris Cité, 75015 Paris, France
David B. Haslam
Division of Infectious Diseases, Center for Inflammation and Tolerance, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA
Thomas Hagan
Division of Infectious Diseases, Center for Inflammation and Tolerance, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA
Suzanne M. Noble
Department of Microbiology and Immunology, University of California, San Francisco School of Medicine, San Francisco, CA 94143, USA
Richard J. Bennett
Molecular Microbiology and Immunology Department, Brown University, Providence, RI 02912, USA
Sing Sing Way
Division of Infectious Diseases, Center for Inflammation and Tolerance, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA; Corresponding author
Summary: Systemic immunity is stringently regulated by commensal intestinal microbes, including the pathobiont Candida albicans. This fungus utilizes various transcriptional and morphological programs for host adaptation, but how this heterogeneity affects immunogenicity remains uncertain. We show that UME6, a transcriptional regulator of filamentation, is essential for intestinal C. albicans-primed systemic Th17 immunity. UME6 deletion and constitutive overexpression strains are non-immunogenic during commensal colonization, whereas immunogenicity is restored by C. albicans undergoing oscillating UME6 expression linked with β-glucan and mannan production. In turn, intestinal reconstitution with these fungal cell wall components restores protective Th17 immunity to mice colonized with UME6-locked variants. These fungal cell wall ligands and commensal C. albicans stimulate Th17 immunity through multiple host pattern recognition receptors, including Toll-like receptor 2 (TLR2), TLR4, Dectin-1, and Dectin-2, which work synergistically for colonization-induced protection. Thus, dynamic gene expression fluctuations by C. albicans during symbiotic colonization are essential for priming host immunity against disseminated infection.
