title: Reduced nicotinamide adenine dinucleotide phosphate oxidase-independent resistance to Aspergillus fumigatus in alveolar macrophages.
abstract: The fungal pathogen Aspergillus fumigatus is responsible for increasing numbers of fatal infections in immune-compromised humans. Alveolar macrophages (AM) are important in the innate defense against aspergillosis, but little is known about their molecular responses to fungal conidia in vivo. We examined transcriptional changes and superoxide release by AM from C57BL/6 and gp91(phox)(-/-) mice in response to conidia. Following introduction of conidia into the lung, microarray analysis of AM showed the transcripts most strongly up-regulated in vivo to encode chemokines and additional genes that play a critical role in neutrophil and monocyte recruitment, indicating that activation of phagocytes represents a critical early response of AM to fungal conidia. Of the 73 AM genes showing > or = 2-fold changes, 8 were also increased in gp91(phox)(-/-) mice by conidia and in C57BL/6 mice by polystyrene beads, suggesting a common innate response to particulate matter. Ingenuity analysis of the microarray data from C57BL/6 mice revealed immune cell signaling and gene expression as primary mechanisms of this response. Despite the well-established importance of phagocyte NADPH oxidase in resisting aspergillosis, we found no evidence of this mechanism in AM following introduction of conidia into the mouse lung using transcriptional, luminometry, or NBT staining analysis. In support of these findings, we observed that AM from C57BL/6 and gp91(phox)(-/-) mice inhibit conidial germination equally in vitro. Our results indicate that early transcription in mouse AM exposed to conidia in vivo targets neutrophil recruitment, and that NADPH oxidase-independent mechanisms in AM contribute to inhibition of conidial germination.
authors.affiliation: Department of Microbiology, Montana State University, Bozeman, MT 59717, USA.
authors.forename: E Jean
authors.initials: EJ
authors.lastname: Cornish
authors.forename: Brady J
authors.initials: BJ
authors.lastname: Hurtgen
authors.forename: Kate
authors.initials: K
authors.lastname: McInnerney
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Burritt
authors.forename: Ross M
authors.initials: RM
authors.lastname: Taylor
authors.forename: James N
authors.initials: JN
authors.lastname: Jarvis
authors.forename: Shirley Y
authors.initials: SY
authors.lastname: Wang
authors.forename: James B
authors.initials: JB
authors.lastname: Burritt
mesh_terms: D000818:Animals; D001228:Aspergillosis / Q000276:immunology*; D001232:Aspergillus fumigatus; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D004797:Enzyme-Linked Immunosorbent Assay; D015870:Gene Expression; D008172:Lung Diseases, Fungal / Q000276:immunology*; D008262:Macrophage Activation / Q000276:immunology; D016676:Macrophages, Alveolar / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D019255:NADPH Oxidases / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013172:Spores, Fungal / Q000276:immunology; D013481:Superoxides / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D012333:RNA, Messenger; D013481:Superoxides; D019255:NADPH Oxidases