title: Hypoxia enhances innate immune activation to Aspergillus fumigatus through cell wall modulation.
abstract: Infection by the human fungal pathogen Aspergillus fumigatus induces hypoxic microenvironments within the lung that can alter the course of fungal pathogenesis. How hypoxic microenvironments shape the composition and immune activating potential of the fungal cell wall remains undefined. Herein we demonstrate that hypoxic conditions increase the hyphal cell wall thickness and alter its composition particularly by augmenting total and surface-exposed β-glucan content. In addition, hypoxia-induced cell wall alterations increase macrophage and neutrophil responsiveness and antifungal activity as judged by inflammatory cytokine production and ability to induce hyphal damage. We observe that these effects are largely dependent on the mammalian β-glucan receptor dectin-1. In a corticosteroid model of invasive pulmonary aspergillosis, A. fumigatus β-glucan exposure correlates with the presence of hypoxia in situ. Our data suggest that hypoxia-induced fungal cell wall changes influence the activation of innate effector cells at sites of hyphal tissue invasion, which has potential implications for therapeutic outcomes of invasive pulmonary aspergillosis.
authors.affiliation: Department of Immunology and Infectious Diseases, Montana State University, Bozeman, MT 59717, USA.
authors.forename: Kelly M
authors.initials: KM
authors.lastname: Shepardson
authors.forename: Lisa Y
authors.initials: LY
authors.lastname: Ngo
authors.forename: Vishukumar
authors.initials: V
authors.lastname: Aimanianda
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Latgé
authors.forename: Bridget M
authors.initials: BM
authors.lastname: Barker
authors.forename: Sara J
authors.initials: SJ
authors.lastname: Blosser
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Iwakura
authors.forename: Tobias M
authors.initials: TM
authors.lastname: Hohl
authors.forename: Robert A
authors.initials: RA
authors.lastname: Cramer
mesh_terms: D000693:Anaerobiosis; D000818:Animals; D001232:Aspergillus fumigatus / Q000166:cytology* / Q000276:immunology / Q000502:physiology*; D002473:Cell Wall / Q000737:chemistry / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D025301:Hyphae / Q000166:cytology / Q000276:immunology / Q000502:physiology; D007113:Immunity, Innate; D037181:Lectins, C-Type / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology; D055732:Pulmonary Aspergillosis / Q000276:immunology / Q000382:microbiology; D047071:beta-Glucans / Q000032:analysis; D000099181:Dectin-1
chemical_list: D016207:Cytokines; D037181:Lectins, C-Type; D047071:beta-Glucans; D000099181:Dectin-1