title: Myeloid derived hypoxia inducible factor 1-alpha is required for protection against pulmonary Aspergillus fumigatus infection.
abstract: Hypoxia inducible factor 1α (HIF1α) is the mammalian transcriptional factor that controls metabolism, survival, and innate immunity in response to inflammation and low oxygen. Previous work established that generation of hypoxic microenvironments occurs within the lung during infection with the human fungal pathogen Aspergillus fumigatus. Here we demonstrate that A. fumigatus stabilizes HIF1α protein early after pulmonary challenge that is inhibited by treatment of mice with the steroid triamcinolone. Utilizing myeloid deficient HIF1α mice, we observed that HIF1α is required for survival and fungal clearance early following pulmonary challenge with A. fumigatus. Unlike previously reported research with bacterial pathogens, HIF1α deficient neutrophils and macrophages were surprisingly not defective in fungal conidial killing. The increase in susceptibility of the myeloid deficient HIF1α mice to A. fumigatus was in part due to decreased early production of the chemokine CXCL1 (KC) and increased neutrophil apoptosis at the site of infection, resulting in decreased neutrophil numbers in the lung. Addition of recombinant CXCL1 restored neutrophil survival and numbers, murine survival, and fungal clearance. These results suggest that there are unique HIF1α mediated mechanisms employed by the host for protection and defense against fungal pathogen growth and invasion in the lung. Additionally, this work supports the strategy of exploring HIF1α as a therapeutic target in specific immunosuppressed populations with fungal infections.
authors.affiliation: Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, United States of America.
authors.forename: Kelly M
authors.initials: KM
authors.lastname: Shepardson
authors.affiliation: Infectious Disease Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Anupam
authors.initials: A
authors.lastname: Jhingran
authors.affiliation: Department of Microbiology and Immunology, Montana State University, Bozeman, Montana, United States of America.
authors.forename: Alayna
authors.initials: A
authors.lastname: Caffrey
authors.affiliation: Department of Microbiology and Immunology, Montana State University, Bozeman, Montana, United States of America.
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: Obar
authors.affiliation: Department of Medicine, University of Vermont College of Medicine, Burlington, Vermont, United States of America.
authors.forename: Benjamin T
authors.initials: BT
authors.lastname: Suratt
authors.affiliation: Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, United States of America.
authors.forename: Brent L
authors.initials: BL
authors.lastname: Berwin
authors.affiliation: Infectious Disease Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Tobias M
authors.initials: TM
authors.lastname: Hohl
authors.affiliation: Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, United States of America.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Cramer
mesh_terms: D000818:Animals; D017209:Apoptosis; D001232:Aspergillus fumigatus / Q000276:immunology*; D015153:Blotting, Western; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D054360:Chemokine CXCL1 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007113:Immunity, Innate / Q000276:immunology*; D007124:Immunoenzyme Techniques; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D008168:Lung / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D022423:Myeloid Cells / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D055732:Pulmonary Aspergillosis / Q000276:immunology / Q000378:metabolism / Q000382:microbiology / Q000517:prevention & control*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D054360:Chemokine CXCL1; C475895:Cxcl1 protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger