HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Cornish, E. J. Articles by Burritt, J. B. Search for Related Content PubMed PubMed Citation Articles by Cornish, E. J. Articles by Burritt, J. B.

Reduced Nicotinamide Adenine Dinucleotide Phosphate Oxidase-Independent Resistance to Aspergillus fumigatus in Alveolar Macrophages¹

E. Jean Cornish^*, Brady J. Hurtgen^*, Kate McInnerney^*, Nancy L. Burritt^*, Ross M. Taylor^*, James N. Jarvis, Shirley Y. Wang and James B. Burritt^2,*

^* Department of Microbiology, Montana State University, Bozeman, MT 59717; and Oklahoma University Health Sciences Center, Oklahoma City, OK 73104

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 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health (NIH) Award 1 R03 AI057931-01 (to J.B.B.), American Heart Association Scientist Development Grant 0630253N (to R.M.T.), and was also made possible by NIH Grant 1 P20 RR-020185-01 from the National Center for Research Resources.

² Address correspondence and reprint requests to Dr. James B. Burritt, Department of Microbiology, Montana State University, 109 Lewis Hall, Bozeman, MT 59717. E-mail address: jburritt{at}montana.edu

³ Abbreviations used in this paper: IPA, invasive pulmonary aspergillosis; AM, alveolar macrophage; PMN, polymorphonuclear neutrophil; qRT-PCR, quantitative RT-PCR; BALF, bronchoalveolar lavage fluid; MCLA, 2-methyl-6-(4-methoxyphenyl)imidazo[1,2-a] pyrazin-3(7H)-one; SOD, superoxide dismutase; HO, heme oxygenase.

This article has been cited by other articles:

				S. J. Park and B. Mehrad Innate Immunity to Aspergillus Species Clin. Microbiol. Rev., October 1, 2009; 22(4): 535 - 551. [Abstract] [Full Text] [PDF]

				M. Bianchi, A. Hakkim, V. Brinkmann, U. Siler, R. A. Seger, A. Zychlinsky, and J. Reichenbach Restoration of NET formation by gene therapy in CGD controls aspergillosis Blood, September 24, 2009; 114(13): 2619 - 2622. [Abstract] [Full Text] [PDF]

				S. J. Park, M. A. Hughes, M. Burdick, R. M. Strieter, and B. Mehrad Early NK Cell-Derived IFN-{gamma} Is Essential to Host Defense in Neutropenic Invasive Aspergillosis J. Immunol., April 1, 2009; 182(7): 4306 - 4312. [Abstract] [Full Text] [PDF]