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

Sarah R Beattie; Kenneth M K Mark; Arsa Thammahong; Laure Nicolas Annick Ries; Sourabh Dhingra; Alayna K Caffrey-Carr; Chao Cheng; Candice C Black; Paul Bowyer; Michael J Bromley; Joshua J Obar; Gustavo H Goldman; Robert A Cramer

doi:10.1371/journal.ppat.1006340

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

Journal article

Open access

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

Sarah R Beattie, Kenneth M K Mark, Arsa Thammahong, Laure Nicolas Annick Ries, Sourabh Dhingra, Alayna K Caffrey-Carr, Chao Cheng, Candice C Black, Paul Bowyer, Michael J Bromley, …

PLoS pathogens, Vol.13(4), pp.e1006340-e1006340

04/2017

DOI: 10.1371/journal.ppat.1006340

PMCID: PMC5411099

PMID: 28423062

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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).

Aspergillosis - microbiology

Aspergillosis - pathology

Aspergillus fumigatus - genetics

Aspergillus fumigatus - physiology

Carbon - metabolism

Catabolite Repression

Disease Progression

Fungal Proteins - genetics

Fungal Proteins - metabolism

Gene Expression Regulation, Fungal - drug effects

Gene Regulatory Networks

Models, Biological

Repressor Proteins - genetics

Repressor Proteins - metabolism

Stress, Physiological

Details

Title: Subtitle: Filamentous fungal carbon catabolite repression supports metabolic plasticity and stress responses essential for disease progression
Creators: Sarah R Beattie - Dartmouth College
Kenneth M K Mark - Dartmouth College
Arsa Thammahong - Dartmouth College
Laure Nicolas Annick Ries - Universidade de São Paulo
Sourabh Dhingra - Dartmouth College
Alayna K Caffrey-Carr - Dartmouth College
Chao Cheng - Dartmouth College
Candice C Black - Dartmouth–Hitchcock Medical Center
Paul Bowyer - University of Manchester
Michael J Bromley - University of Manchester
Joshua J Obar - Dartmouth College
Gustavo H Goldman - Universidade de São Paulo
Robert A Cramer - Dartmouth College
Resource Type: Journal article
Publication Details: PLoS pathogens, Vol.13(4), pp.e1006340-e1006340
DOI: 10.1371/journal.ppat.1006340
PMID: 28423062
PMCID: PMC5411099
NLM abbreviation: PLoS Pathog
ISSN: 1553-7366
eISSN: 1553-7374
Grant note: T32 AI007519 / NIAID NIH HHS P30 GM106394 / NIGMS NIH HHS R01 AI081838 / NIAID NIH HHS T32 GM008704 / NIGMS NIH HHS
Language: English
Date published: 04/2017
Academic Unit: Stead Family Department of Pediatrics; Infectious Disease (Pediatrics)
Record Identifier: 9984353941702771

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