Regulation of airway fumarate by host and pathogen promotes S. aureus pneumonia
Ying-Tsun Chen1, Zihua Liu2, Dario Fucich1
1Department of Pediatrics, Columbia University, New York, NY 10032, USA.
Abstract:
Staphylococcus aureus is a leading cause of healthcare-associated pneumonia, contributing significantly to morbidity and mortality worldwide. As a ubiquitous colonizer of the upper respiratory tract, S. aureus must undergo substantial metabolic adaptation to achieve persistent infection in the distinctive microenvironment of the lung. We observed that fumC, which encodes the enzyme that converts fumarate to malate, is highly conserved with low mutation rates in S. aureus isolates from chronic lung infections. Fumarate, a pro-inflammatory metabolite produced by macrophages during infection, is regulated by the host fumarate hydratase (FH) to limit inflammation. Here, we demonstrate that fumarate, which accumulates in the chronically infected lung, is detrimental to S. aureus, blocking primary metabolic pathways such as glycolysis and oxidative phosphorylation (OXPHOS). This creates a metabolic bottleneck that drives staphylococcal FH (FumC) activity for airway adaptation. FumC not only degrades fumarate but also directs its utilization into critical pathways including the tricarboxylic acid (TCA) cycle, gluconeogenesis and hexosamine synthesis to maintain metabolic fitness and form a protective biofilm. Itaconate, another abundant immunometabolite in the infected airway enhances FumC activity, in synergy with fumarate. In a mouse model of pneumonia, a ΔfumC mutant displays significant attenuation compared to its parent and complemented strains, particularly in fumarate- and itaconate-replete conditions. Our findings underscore the pivotal role of immunometabolites in promoting S. aureus pulmonary adaptation.
Insights
Staphylococcus aureus uses the fumC enzyme to metabolize harmful fumarate in the lungs, enabling adaptation and biofilm formation during pneumonia. This adaptation is crucial for survival in the infected airway environment.
Area of Science:
- Microbiology
- Immunology
- Metabolic Adaptation
Background:
- Staphylococcus aureus is a major cause of hospital-acquired pneumonia.
- The bacterium must adapt metabolically to survive in the lung's unique environment.
- Fumarate, a host-produced metabolite, can be detrimental to S. aureus.
Purpose of the Study:
- Investigate the role of the fumC gene and its product in S. aureus adaptation during pulmonary infection.
- Determine how S. aureus utilizes fumarate and other host metabolites for survival and virulence.
- Elucidate the mechanisms by which S. aureus overcomes metabolic challenges in the infected lung.
Main Methods:
- Analysis of fumC conservation in clinical isolates.
- In vitro metabolic assays assessing the impact of fumarate on S. aureus pathways.
- Gene deletion mutant construction and characterization (ΔfumC).
- In vivo mouse model of Staphylococcus aureus pneumonia.
Main Results:
- The fumC gene is highly conserved in chronic lung infection isolates.
- Fumarate accumulation blocks S. aureus glycolysis and oxidative phosphorylation (OXPHOS).
- Staphylococcal fumarate hydratase (FumC) activity is essential for degrading fumarate and directing its carbon into central metabolic pathways (TCA cycle, gluconeogenesis, hexosamine synthesis).
- Itaconate enhances FumC activity.
- A ΔfumC mutant showed significant attenuation in a mouse pneumonia model, especially under fumarate- and itaconate-replete conditions.
Conclusions:
- Staphylococcus aureus FumC is critical for pulmonary adaptation by metabolizing detrimental fumarate and utilizing it for biosynthesis.
- Host immunometabolites like fumarate and itaconate shape bacterial adaptation strategies.
- Targeting FumC or related metabolic pathways could be a novel therapeutic strategy against S. aureus pneumonia.
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