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

PLoS Pathogens

Sourabh Dhingra¹  Alayna K. Caffrey-Carr¹  Arsa Thammahong¹  Sarah R. Beattie¹  Chao Cheng²  Candice C. Black³  Kenneth M. K. Mark³  Joshua J. Obar⁴  Laure Nicolas Annick Ries⁵  Michael J. Bromley⁶  Gustavo H. Goldman⁷  Robert A. Cramer⁷  Paul Bowyer⁸ 

[1] Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, United States of America;Department of Microbiology and Immunology, Montana State University, Bozeman, Montana, United States of America;Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, United States of America;Department of Pathology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, United States of America;Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Brazil;Institute for Quantitative Biomedical Sciences, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, United States of America;Manchester Fungal Infection Group, School of Biological Sciences, University of Manchester, Manchester, United Kingdom;Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, United States of America

关键词: Fungal diseases;    Aspergillus fumigatus;    Glucose;    Glucose metabolism;    Fungal genetics;    Mouse models;    Fungal pathogens;    C;    ida albicans;   

DOI  :  10.1371/journal.ppat.1006340

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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).

【 授权许可】

CC BY