title: A crucial role for tryptophan catabolism at the host/Candida albicans interface.
abstract: By mediating tryptophan catabolism, the enzyme indoleamine 2,3-dioxygenase (IDO) has a complex role in immunoregulation in infection, pregnancy, autoimmunity, transplantation, and neoplasia. We hypothesized that IDO might affect the outcome of the infection in mice infected with Candida albicans by virtue of its potent regulatory effects on inflammatory and T cell responses. IDO expression was examined in mice challenged with the fungus along with the consequences of its blockade by in vivo treatment with an enzyme inhibitor. We found that IDO activity was induced at sites of infection as well as in dendritic cells and effector neutrophils via IFN-gamma- and CTLA-4-dependent mechanisms. IDO inhibition greatly exacerbated infection and associated inflammatory pathology as a result of deregulated innate and adaptive/regulatory immune responses. However, a role for tryptophan catabolism was also demonstrated in a fungus-autonomous fashion; its blockade in vitro promoted yeast-to-hyphal transition. These results provide novel mechanistic insights into complex events that, occurring at the fungus/pathogen interface, relate to the dynamics of host adaptation to the fungus. The production of IFN-gamma may be squarely placed at this interface, where IDO activation probably exerts a fine control over fungal morphology as well as inflammatory and adaptive antifungal responses.
authors.affiliation: Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Bozza
authors.forename: Francesca
authors.initials: F
authors.lastname: Fallarino
authors.forename: Lucia
authors.initials: L
authors.lastname: Pitzurra
authors.forename: Teresa
authors.initials: T
authors.lastname: Zelante
authors.forename: Claudia
authors.initials: C
authors.lastname: Montagnoli
authors.forename: Silvia
authors.initials: S
authors.lastname: Bellocchio
authors.forename: Paolo
authors.initials: P
authors.lastname: Mosci
authors.forename: Carmine
authors.initials: C
authors.lastname: Vacca
authors.forename: Paolo
authors.initials: P
authors.lastname: Puccetti
authors.forename: Luigina
authors.initials: L
authors.lastname: Romani
mesh_terms: D000818:Animals; D002176:Candida albicans / Q000166:cytology / Q000201:enzymology / Q000276:immunology*; D002177:Candidiasis / Q000201:enzymology* / Q000276:immunology* / Q000473:pathology; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis / Q000502:physiology; D015536:Down-Regulation / Q000276:immunology; D004791:Enzyme Inhibitors / Q000737:chemistry; D005260:Female; D005756:Gastritis / Q000201:enzymology / Q000382:microbiology / Q000473:pathology; D007113:Immunity, Innate; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D018836:Inflammation Mediators / Q000502:physiology; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D007674:Kidney Diseases / Q000201:enzymology / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000473:pathology; D018417:Th1 Cells / Q000473:pathology; D018418:Th2 Cells / Q000473:pathology; D014364:Tryptophan / Q000031:analogs & derivatives* / Q000378:metabolism / Q000502:physiology*; D014366:Tryptophan Oxygenase / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D015854:Up-Regulation / Q000276:immunology
chemical_list: D016207:Cytokines; D004791:Enzyme Inhibitors; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D018836:Inflammation Mediators; C028129:tryptophan methyl ester; D007371:Interferon-gamma; D014364:Tryptophan; D014366:Tryptophan Oxygenase