RNAseq Analysis of Aspergillus Fumigatus in Blood Reveals a Just Wait and See Resting Stage Behavior

Overview

Journal BMC Genomics

Publisher Biomed Central

Specialty Genetics

Date 2015 Aug 28

PMID 26311470

Citations 16

Authors

Henriette Irmer

Sonia Tarazona

Christoph Sasse

Patrick Olbermann

Jurgen Loeffler

Sven Krappmann

Ana Conesa

Gerhard H Braus

Affiliations

Soon will be listed here.

Abstract

Background: Invasive aspergillosis is started after germination of Aspergillus fumigatus conidia that are inhaled by susceptible individuals. Fungal hyphae can grow in the lung through the epithelial tissue and disseminate hematogenously to invade into other organs. Low fungaemia indicates that fungal elements do not reside in the bloodstream for long.

Results: We analyzed whether blood represents a hostile environment to which the physiology of A. fumigatus has to adapt. An in vitro model of A. fumigatus infection was established by incubating mycelium in blood. Our model allowed to discern the changes of the gene expression profile of A. fumigatus at various stages of the infection. The majority of described virulence factors that are connected to pulmonary infections appeared not to be activated during the blood phase. Three active processes were identified that presumably help the fungus to survive the blood environment in an advanced phase of the infection: iron homeostasis, secondary metabolism, and the formation of detoxifying enzymes.

Conclusions: We propose that A. fumigatus is hardly able to propagate in blood. After an early stage of sensing the environment, virtually all uptake mechanisms and energy-consuming metabolic pathways are shut-down. The fungus appears to adapt by trans-differentiation into a resting mycelial stage. This might reflect the harsh conditions in blood where A. fumigatus cannot take up sufficient nutrients to establish self-defense mechanisms combined with significant growth.

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References

Cerqueira G, Arnaud M, Inglis D, Skrzypek M, Binkley G, Simison M . The Aspergillus Genome Database: multispecies curation and incorporation of RNA-Seq data to improve structural gene annotations. Nucleic Acids Res. 2013; 42(Database issue):D705-10. PMC: 3965050. DOI: 10.1093/nar/gkt1029. View

David H, Hofmann G, Oliveira A, Jarmer H, Nielsen J . Metabolic network driven analysis of genome-wide transcription data from Aspergillus nidulans. Genome Biol. 2006; 7(11):R108. PMC: 1794588. DOI: 10.1186/gb-2006-7-11-r108. View

. Standards of medical care in diabetes--2012. Diabetes Care. 2011; 35 Suppl 1:S11-63. PMC: 3632172. DOI: 10.2337/dc12-s011. View

Muller S, Baldin C, Groth M, Guthke R, Kniemeyer O, Brakhage A . Comparison of transcriptome technologies in the pathogenic fungus Aspergillus fumigatus reveals novel insights into the genome and MpkA dependent gene expression. BMC Genomics. 2012; 13:519. PMC: 3505472. DOI: 10.1186/1471-2164-13-519. View

McCormick A, Loeffler J, Ebel F . Aspergillus fumigatus: contours of an opportunistic human pathogen. Cell Microbiol. 2010; 12(11):1535-43. DOI: 10.1111/j.1462-5822.2010.01517.x. View

Steinbach W, Marr K, Anaissie E, Azie N, Quan S, Meier-Kriesche H . Clinical epidemiology of 960 patients with invasive aspergillosis from the PATH Alliance registry. J Infect. 2012; 65(5):453-64. DOI: 10.1016/j.jinf.2012.08.003. View

Fortwendel J, Fuller K, Stephens T, Bacon W, Askew D, Rhodes J . Aspergillus fumigatus RasA regulates asexual development and cell wall integrity. Eukaryot Cell. 2008; 7(9):1530-9. PMC: 2547073. DOI: 10.1128/EC.00080-08. View

Hynes M, Draht O, Davis M . Regulation of the acuF gene, encoding phosphoenolpyruvate carboxykinase in the filamentous fungus Aspergillus nidulans. J Bacteriol. 2001; 184(1):183-90. PMC: 134779. DOI: 10.1128/JB.184.1.183-190.2002. View

Dent K, Weber B, Benedik M, Sewell B . The cyanide hydratase from Neurospora crassa forms a helix which has a dimeric repeat. Appl Microbiol Biotechnol. 2008; 82(2):271-8. DOI: 10.1007/s00253-008-1735-4. View

10.

Dowzer C, Kelly J . Analysis of the creA gene, a regulator of carbon catabolite repression in Aspergillus nidulans. Mol Cell Biol. 1991; 11(11):5701-9. PMC: 361941. DOI: 10.1128/mcb.11.11.5701-5709.1991. View

11.

Clemons K, Stevens D . The contribution of animal models of aspergillosis to understanding pathogenesis, therapy and virulence. Med Mycol. 2005; 43 Suppl 1:S101-10. DOI: 10.1080/13693780500051919. View

12.

Gautam P, Shankar J, Madan T, Sirdeshmukh R, Sundaram C, Gade W . Proteomic and transcriptomic analysis of Aspergillus fumigatus on exposure to amphotericin B. Antimicrob Agents Chemother. 2008; 52(12):4220-7. PMC: 2592866. DOI: 10.1128/AAC.01431-07. View

13.

Chung D, Barker B, Carey C, Merriman B, Werner E, Lechner B . ChIP-seq and in vivo transcriptome analyses of the Aspergillus fumigatus SREBP SrbA reveals a new regulator of the fungal hypoxia response and virulence. PLoS Pathog. 2014; 10(11):e1004487. PMC: 4223079. DOI: 10.1371/journal.ppat.1004487. View

14.

Lewis R, Wiederhold N . Murine model of invasive aspergillosis. Methods Mol Med. 2005; 118:129-42. DOI: 10.1385/1-59259-943-5:129. View

15.

Pedrajas J, Kosmidou E, Miranda-Vizuete A, Gustafsson J, Wright A, Spyrou G . Identification and functional characterization of a novel mitochondrial thioredoxin system in Saccharomyces cerevisiae. J Biol Chem. 1999; 274(10):6366-73. DOI: 10.1074/jbc.274.10.6366. View

16.

Almeida R, Wilson D, Hube B . Candida albicans iron acquisition within the host. FEMS Yeast Res. 2009; 9(7):1000-12. DOI: 10.1111/j.1567-1364.2009.00570.x. View

17.

Nierman W, Pain A, Anderson M, Wortman J, Kim H, Arroyo J . Genomic sequence of the pathogenic and allergenic filamentous fungus Aspergillus fumigatus. Nature. 2005; 438(7071):1151-6. DOI: 10.1038/nature04332. View

18.

Willger S, Puttikamonkul S, Kim K, Burritt J, Grahl N, Metzler L . A sterol-regulatory element binding protein is required for cell polarity, hypoxia adaptation, azole drug resistance, and virulence in Aspergillus fumigatus. PLoS Pathog. 2008; 4(11):e1000200. PMC: 2572145. DOI: 10.1371/journal.ppat.1000200. View

19.

Arst Jr H, Cove D . Nitrogen metabolite repression in Aspergillus nidulans. Mol Gen Genet. 1973; 126(2):111-41. DOI: 10.1007/BF00330988. View

20.

da Silva Ferreira M, Malavazi I, Savoldi M, Brakhage A, Goldman M, Kim H . Transcriptome analysis of Aspergillus fumigatus exposed to voriconazole. Curr Genet. 2006; 50(1):32-44. DOI: 10.1007/s00294-006-0073-2. View