First Author | Shepardson KM | Year | 2014 |
Journal | PLoS Pathog | Volume | 10 |
Issue | 9 | Pages | e1004378 |
PubMed ID | 25255025 | Mgi Jnum | J:248179 |
Mgi Id | MGI:5919140 | Doi | 10.1371/journal.ppat.1004378 |
Citation | Shepardson KM, et al. (2014) Myeloid derived hypoxia inducible factor 1-alpha is required for protection against pulmonary Aspergillus fumigatus infection. PLoS Pathog 10(9):e1004378 |
abstractText | Hypoxia inducible factor 1alpha (HIF1alpha) 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 HIF1alpha protein early after pulmonary challenge that is inhibited by treatment of mice with the steroid triamcinolone. Utilizing myeloid deficient HIF1alpha mice, we observed that HIF1alpha is required for survival and fungal clearance early following pulmonary challenge with A. fumigatus. Unlike previously reported research with bacterial pathogens, HIF1alpha deficient neutrophils and macrophages were surprisingly not defective in fungal conidial killing. The increase in susceptibility of the myeloid deficient HIF1alpha 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 HIF1alpha 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 HIF1alpha as a therapeutic target in specific immunosuppressed populations with fungal infections. |