Filamentous fungal carbon catabolite repression supports metabolic plasticity and stress responses essential for disease progression.

TitleFilamentous fungal carbon catabolite repression supports metabolic plasticity and stress responses essential for disease progression.
Publication TypeJournal Article
Year of Publication2017
AuthorsBeattie, SR, Mark, KMK, Thammahong, A, Ries, LNicolas An, Dhingra, S, Caffrey-Carr, AK, Cheng, C, Black, CC, Bowyer, P, Bromley, MJ, Obar, JJ, Goldman, GH, Cramer, RA
JournalPLoS Pathog
Volume13
Issue4
Paginatione1006340
Date Published2017 Apr
ISSN1553-7374
KeywordsAspergillosis, Aspergillus fumigatus, Carbon, Catabolite Repression, Disease Progression, Fungal Proteins, Gene Expression Regulation, Fungal, Gene Regulatory Networks, Models, Biological, Repressor Proteins, Stress, Physiological
Abstract

Aspergillus fumigatus is responsible for a disproportionate number of invasive mycosis cases relative to other common filamentous fungi. While many fungal factors critical for infection establishment are known, genes essential for disease persistence and progression are ill defined. We propose that fungal factors that promote navigation of the rapidly changing nutrient and structural landscape characteristic of disease progression represent untapped clinically relevant therapeutic targets. To this end, we find that A. fumigatus requires a carbon catabolite repression (CCR) mediated genetic network to support in vivo fungal fitness and disease progression. While CCR as mediated by the transcriptional repressor CreA is not required for pulmonary infection establishment, loss of CCR inhibits fungal metabolic plasticity and the ability to thrive in the dynamic infection microenvironment. Our results suggest a model whereby CCR in an environmental filamentous fungus is dispensable for initiation of pulmonary infection but essential for infection maintenance and disease progression. Conceptually, we argue these data provide a foundation for additional studies on fungal factors required to support fungal fitness and disease progression and term such genes and factors, DPFs (disease progression factors).

DOI10.1371/journal.ppat.1006340
Alternate JournalPLoS Pathog.
PubMed ID28423062
PubMed Central IDPMC5411099
Grant ListP30 GM106394 / GM / NIGMS NIH HHS / United States
R01 AI081838 / AI / NIAID NIH HHS / United States
T32 AI007519 / AI / NIAID NIH HHS / United States
T32 GM008704 / GM / NIGMS NIH HHS / United States