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Identification and Characterization of Immunogenic RNA Species in HDM Allergens that Modulate Eosinophilic Lung Inflammation
Published on: May 30, 2020
Identification of Histoplasma capsulatum transcripts induced in response to reactive nitrogen species
M Paige Nittler1, Davina Hocking-Murray, Catherine K Foo
1Department of Microbiology and Immunology, University of California-San Francisco, San Francisco, CA 94143-0414, USA.
Abstract:
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 > or = 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.
Insights
Histoplasma capsulatum survives host immune defenses by responding to reactive nitrogen species (RNS). This study identified key genes, including a nitric oxide reductase, enabling fungal survival during nitrosative stress.
Area of Science:
- Mycology
- Immunology
- Molecular Biology
Background:
- Histoplasma capsulatum is a pathogenic fungus that infects host macrophages.
- Nitric oxide (NO) produced during adaptive immunity restricts fungal replication.
- H. capsulatum establishes persistent infections, suggesting survival mechanisms against reactive nitrogen species (RNS).
Purpose of the Study:
- To investigate the transcriptional response of H. capsulatum to RNS.
- To identify genes and pathways involved in fungal survival under nitrosative stress.
Main Methods:
- Shotgun genomic microarray to identify RNS-induced transcripts.
- High-density oligonucleotide tiling arrays to determine genomic boundaries of induced transcripts.
- Ectopic gene expression to assess functional significance.
Main Results:
- Identified 695 microarray clones and 153 RNS-induced transcripts.
- Induced genes are involved in iron acquisition, energy production, stress response, protein folding, DNA repair, and NO detoxification.
- Ectopic expression of a P450 nitric oxide reductase homologue conferred increased resistance to RNS.
Conclusions:
- H. capsulatum possesses pathways to cope with RNS-induced damage.
- These identified pathways are crucial for fungal survival and pathogenesis despite host immune responses.
