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Vol. 16, Issue 10, 4792-4813, October 2005

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Identification of Histoplasma capsulatum Transcripts Induced in Response to Reactive Nitrogen Species

Department of Microbiology and Immunology, University of California-San Francisco, San Francisco, CA 94143-0414

Submitted May 18, 2005; Revised June 30, 2005; Accepted July 11, 2005
Monitoring Editor: Mark Solomon

The pathogenic fungus Histoplasma capsulatum escapes innate immune defenses and colonizes host macrophages during infection. After the onset of adaptive immunity, the production of the antimicrobial effector nitric oxide (^.NO) restricts H. capsulatum replication. However, H. capsulatum can establish persistent infections, indicating that it survives in the host despite exposure to reactive nitrogen species (RNS). To understand how H. capsulatum responds to RNS, we determined the transcriptional profile of H. capsulatum to ^.NO-generating compounds using a shotgun genomic microarray. We identified 695 microarray clones that were induced 4-fold upon nitrosative stress. Because our microarray clones were generated from random fragments of genomic DNA, they did not necessarily correspond to H. capsulatum open reading frames. To identify induced genes, we used high-density oligonucleotide tiling arrays to determine the genomic boundaries and coding strand of 153 RNS-induced transcripts. Homologues of these genes in other organisms are involved in iron acquisition, energy production, stress response, protein folding/degradation, DNA repair, and ^.NO detoxification. Ectopic expression of one of these genes, a P450 nitric oxide reductase homologue, was sufficient to increase resistance of H. capsulatum to RNS in culture. We propose that H. capsulatum uses the pathways identified here to cope with RNS-induced damage during pathogenesis.

Abbreviations used: DPTA NONOate, dipropylenetriamine NONOate; GSNO, S-nitrosoglutathione; IFN, interferon; NIT, nitrosative stress-induced transcript; ^.NO, nitric oxide; NOS2, nitric oxide synthase 2; RNS, reactive nitrogen species; ROS, reactive oxygen species.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

Address correspondence to: Anita Sil (sil{at}cgl.ucsf.edu).

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