Journal
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY
Volume 61, Issue 2, Pages 185-197Publisher
AMER THORACIC SOC
DOI: 10.1165/rcmb.2018-0389OC
Keywords
bacterial metabolic adaptation; chronic pulmonary infection; Staphylococcus aureus; cystic fibrosis
Funding
- Cystic Fibrosis Foundation (CFF) grant [CFF Prince 18G0]
- National Institutes of Health (NIH) [R35HL135800, S10RR027050]
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Methicillin-resistant Staphylococcus aureus (MRSA) is a versatile human pathogen that is associated with diverse types of infections ranging from benign colonization to sepsis. We postulated that MRSA must undergo specific genotypic and phenotypic changes to cause chronic pulmonary disease. We investigated how MRSA adapts to the human airway to establish chronic infection, as occurs during cystic fibrosis (CF). MRSA isolates from patients with CF that were collected over a 4-year period were analyzed by whole-genome sequencing, transcriptional analysis, and metabolic studies. Persistent MRSA infection was associated with staphylococcal metabolic adaptation, but not changes in immunogenicity. Adaptation was characterized by selective use of the tricarboxylic acid cycle cycle and generation of biofilm, a means of limiting oxidant stress. Increased transcription of specific metabolic genes was conserved in all host-adapted strains, most notably a 10,000-fold increase in fumC, which catalyzes the interconversion of fumarate and malate. Elevated fumarate levels promoted in vitro biofilm production in clinical isolates. Host-adapted strains preferred to assimilate glucose polymers and pyruvate, which can be metabolized to generate N-acetylglucosamine polymers that comprise biofilm. MRSA undergoes substantial metabolic adaptation to the human airway to cause chronic pulmonary infection, and selected metabolites may be useful therapeutically to inhibit infection.
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