Aspergillus fumigatus tryptophan metabolic route differently affects host immunity
Teresa Zelante, Tsokyi Choera, Anne Beauvais, Francesca Fallarino, Giuseppe Paolicelli, Giuseppe Pieraccini, Marco Pieroni, Claudia Galosi, Claudia Beato, Antonella De Luca, Francesca Boscaro, Riccardo Romoli, Xin Liu, Adilia Warris, Paul E. Verweij, Eloise Ballard, Monica Borghi, Marilena Pariano, Gabriele Costantino, Mario Calvitti, Carmine Vacca, Vasileios Oikonomou, Marco Gargaro, Alicia Y. W. Wong, Louis Boon, Marcel den Hartog, Zdeněk Spáčil, Paolo Puccetti, Jean‐Paul Latgé, Nancy P. Keller, Luigina Romani
Abstract
Indoleamine 2,3-dioxygenases (IDOs) degrade l-tryptophan to kynurenines and drive the de novo synthesis of nicotinamide adenine dinucleotide. Unsurprisingly, various invertebrates, vertebrates, and even fungi produce IDO. In mammals, IDO1 also serves as a homeostatic regulator, modulating immune response to infection via local tryptophan deprivation, active catabolite production, and non-enzymatic cell signaling. Whether fungal Idos have pleiotropic functions that impact on host-fungal physiology is unclear. Here, we show that Aspergillus fumigatus possesses three ido genes that are expressed under conditions of hypoxia or tryptophan abundance. Loss of these genes results in increased fungal pathogenicity and inflammation in a mouse model of aspergillosis, driven by an alternative tryptophan degradation pathway to indole derivatives and the host aryl hydrocarbon receptor. Fungal tryptophan metabolic pathways thus cooperate with the host xenobiotic response to shape host-microbe interactions in local tissue microenvironments.