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Genes differentially expressed in conidia and hyphae of Aspergillus fumigatus upon exposure to human neutrophils.

ABSTRACT: BACKGROUND:Aspergillus fumigatus is the most common etiologic agent of invasive aspergillosis in immunocompromised patients. Several studies have addressed the mechanism involved in host defense but only few have investigated the pathogen's response to attack by the host cells. To our knowledge, this is the first study that investigates the genes differentially expressed in conidia vs hyphae of A. fumigatus in response to neutrophils from healthy donors as well as from those with chronic granulomatous disease (CGD) which are defective in the production of reactive oxygen species. METHODOLOGY/PRINCIPAL FINDINGS:Transcriptional profiles of conidia and hyphae exposed to neutrophils, either from normal donors or from CGD patients, were obtained by using the genome-wide microarray. Upon exposure to either normal or CGD neutrophils, 244 genes were up-regulated in conidia but not in hyphae. Several of these genes are involved in the degradation of fatty acids, peroxisome function and the glyoxylate cycle which suggests that conidia exposed to neutrophils reprogram their metabolism to adjust to the host environment. In addition, the mRNA levels of four genes encoding proteins putatively involved in iron/copper assimilation were found to be higher in conidia and hyphae exposed to normal neutrophils compared to those exposed to CGD neutrophils. Deletants in several of the differentially expressed genes showed phenotypes related to the proposed functions, i.e. deletants of genes involved in fatty acid catabolism showed defective growth on fatty acids and the deletants of iron/copper assimilation showed higher sensitivity to the oxidative agent menadione. None of these deletants, however, showed reduced resistance to neutrophil attack. CONCLUSION:This work reveals the complex response of the fungus to leukocytes, one of the major host factors involved in antifungal defense, and identifies fungal genes that may be involved in establishing or prolonging infections in humans.

SUBMITTER: Sugui JA

PROVIDER: S-EPMC2481287 | biostudies-literature | 2008 Jul

REPOSITORIES: biostudies-literature

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Genes differentially expressed in conidia and hyphae of Aspergillus fumigatus upon exposure to human neutrophils.

Sugui Janyce A JA Kim H Stanley HS Zarember Kol A KA Chang Yun C YC Gallin John I JI Nierman Willian C WC Kwon-Chung Kyung J KJ

PloS one 20080709 7

<h4>Background</h4>Aspergillus fumigatus is the most common etiologic agent of invasive aspergillosis in immunocompromised patients. Several studies have addressed the mechanism involved in host defense but only few have investigated the pathogen's response to attack by the host cells. To our knowledge, this is the first study that investigates the genes differentially expressed in conidia vs hyphae of A. fumigatus in response to neutrophils from healthy donors as well as from those with chronic ...[more]

PMID: 18648542

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Project description:BackgroundPersonal exposure to fungal bioaerosols derived from contaminated building materials or agricultural commodities may induce or exacerbate a variety of adverse health effects. The genomic mechanisms that underlie pulmonary immune responses to fungal bioaerosols have remained unclear.ObjectiveThe impact of fungal viability on the pulmonary microRNA and messenger RNA profiles that regulate murine immune responses was evaluated following subchronic inhalation exposure to Aspergillus fumigatus conidia.MethodsThree groups of naïve B6C3F1/N mice were exposed via nose-only inhalation to A. fumigatus viable conidia, heat-inactivated conidia (HIC), or HEPA-filtered air twice a week for 13 weeks. Total RNA was isolated from whole lung 24 and 48 h postfinal exposure and was further processed for gene expression and microRNA array analysis. The molecular network pathways between viable and HIC groups were evaluated.ResultsComparison of data sets revealed increased Il4, Il13 and Il33 expression in mice exposed to viable vs. HIC. Of 415 microRNAs detected, approximately 50% were altered in mice exposed to viable vs. HIC 48 h postexposure. Significantly down-regulated (P ≤ 0.05) miR-29a-3p was predicted to regulate TGF-β3 and Clec7a, genes involved in innate responses to viable A. fumigatus. Also significantly down-regulated (P ≤ 0.05), miR-23b-3p regulates genes involved in pulmonary IL-13 and IL-33 responses and SMAD2, downstream of TGF-β signalling. Using Ingenuity Pathway Analysis, a novel interaction was identified between viable conidia and SMAD2/3.Conclusions and clinical relevanceExamination of the pulmonary genetic profiles revealed differentially expressed genes and microRNAs following subchronic inhalation exposure to A. fumigatus. MicroRNAs regulating genes involved in the pulmonary immune responses were those with the greatest fold change. Specifically, germinating A. fumigatus conidia were associated with Clec7a and were predicted to interact with Il13 and Il33. Furthermore, altered microRNAs may serve as potential biomarkers to evaluate fungal exposure.

Dataset Information

Genes differentially expressed in conidia and hyphae of Aspergillus fumigatus upon exposure to human neutrophils.

Publications

Genes differentially expressed in conidia and hyphae of Aspergillus fumigatus upon exposure to human neutrophils.

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