ABSTRACT
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.
Subject(s)
Cystic Fibrosis/microbiology , Lung Diseases/microbiology , Methicillin-Resistant Staphylococcus aureus/metabolism , Pneumonia, Staphylococcal/microbiology , Staphylococcal Infections/microbiology , Acetylglucosamine/metabolism , Adult , Animals , Biofilms , Bronchi/metabolism , Bronchoalveolar Lavage Fluid , Cystic Fibrosis/metabolism , Cytokines/metabolism , Female , Fumarates/metabolism , Gentamicins/pharmacology , Glucose/metabolism , Humans , Lung Diseases/metabolism , Malates/metabolism , Male , Mice , Mice, Inbred C57BL , Middle Aged , Phylogeny , Pneumonia, Staphylococcal/metabolism , Pyruvic Acid/metabolism , Staphylococcal Infections/metabolism , Transcription, Genetic , Tricarboxylic Acids/metabolism , Whole Genome SequencingABSTRACT
BACKGROUND: Individuals with cystic fibrosis (CF) are at high risk for depression and anxiety, which are associated with worse medical outcomes. Novel therapies for CF hold great promise for improving physical health, but the effects of these therapies on mental health remain poorly understood. OBJECTIVE: This review aims to familiarize psychiatrists with the potential effect of novel CF therapies on depression and anxiety. METHODS: We discuss novel therapies that directly target the mutant CF protein, the CF transmembrane regulator (CFTR), which are called CFTR modulators. We summarize depression and anxiety screening and treatment guidelines under implementation in accredited CF centers. Case vignettes highlight the complexities of caring for individuals with CF with comorbid depression and anxiety, including patients experiencing worsening depression and anxiety proximate to initiation of CFTR modulator therapy, and management of drug-drug interactions. CONCLUSIONS: Although CFTR modulator therapies provide hope for improving clinical outcomes, worsening depression and anxiety occurs in some patients when starting these novel agents. This phenomenon may be multifactorial, with hypothesized contributions from CFTR modulator-psychotropic medication interactions, direct effects of CFTR modulators on central nervous system function, the psychologic effect of starting a potentially life-altering drug, and typical triggers of depression and anxiety such as stress, pain, and inflammation. The medical and psychiatric complexity of many individuals with CF warrants more direct involvement of mental health specialists on the multidisciplinary CF team. Inclusion of mental health variables in patients with CF registries will facilitate further examination at an epidemiologic level.