title: Histoplasma capsulatum preferentially induces IDO in the lung.
abstract: Indoleamine 2,3 dioxygenase (IDO) plays an important role in immunoregulation as it is involved in downregulating immune responses to infections. We sought to characterize IDO activity in histoplasmosis and to do so, C57Bl6 mice were infected intranasally with Histoplasma capsulatum. After infection, lung and spleen IDO activity was assessed by HPLC and IDO expression by qRT-PCR. The distribution of IDO was determined by immunohistochemical staining. Cytokine levels were measured in lung and spleen homogenates using cytokine bead array. Fungal burden was quantified by culture. Subcutaneous pellets containing methyltryptophane (1-MT) were employed to inhibit IDO in vivo. Histoplasma infection strongly induced functional lung IDO, with activity at its highest at weeks 1 and 2 and then decreased thereafter as the mice cleared the infection. Lung IDO activity positively correlated with the fungal burden (Rho = 0.845), interferon-γ (Rho = 0.839) and tumor necrosis factor-α (Rho = 0.791) levels, P < 0.001. In contrast, spleen IDO activity was not induced despite high infection burden and cytokine levels. IDO expressing cells were predominately located at the ring edge of Histoplasma-induced granulomas. IDO inhibition prior to infection reduced fungal burdens and inflammation in lungs and spleen. Histoplasma preferentially induces lung IDO, as early as one week after infection. IDO appears to modulate the immune response to Histoplasma infection.
authors.affiliation: Indiana University School of Medicine and Roudebush Veterans' Administration Medical Center, Pulmonary Critical Care Medicine, Indianapolis, Indiana 46202, USA. chage@iupui.edu@iupui.edu
authors.forename: Chadi A
authors.initials: CA
authors.lastname: Hage
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Horan
authors.forename: Michelle
authors.initials: M
authors.lastname: Durkin
authors.forename: Patricia
authors.initials: P
authors.lastname: Connolly
authors.forename: Zeruesenay
authors.initials: Z
authors.lastname: Desta
authors.forename: Todd C
authors.initials: TC
authors.lastname: Skaar
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Knox
authors.forename: L Joseph
authors.initials: LJ
authors.lastname: Wheat
mesh_terms: D000818:Animals; D002851:Chromatography, High Pressure Liquid; D015169:Colony Count, Microbial; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006658:Histoplasma / Q000276:immunology* / Q000472:pathogenicity*; D006660:Histoplasmosis / Q000276:immunology* / Q000473:pathology*; D007150:Immunohistochemistry; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000096:biosynthesis*; D008168:Lung / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D060888:Real-Time Polymerase Chain Reaction; D013154:Spleen / Q000382:microbiology / Q000473:pathology
chemical_list: D016207:Cytokines; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase