Abstract
The commensal fungus Candida albicans often causes life-threatening infections in patients who are immunocompromised with high mortality. A prominent but poorly understood risk factor for the C. albicans commensal‒pathogen transition is the use of broad-spectrum antibiotics. Here, we report that β-lactam antibiotics cause bacteria to release significant quantities of peptidoglycan fragments that potently induce the invasive hyphal growth of C. albicans. We identify several active peptidoglycan subunits, including tracheal cytotoxin, a molecule produced by many Gram-negative bacteria, and fragments purified from the cell wall of Gram-positive Staphylococcus aureus. Feeding mice with β-lactam antibiotics causes a peptidoglycan storm that transforms the gut from a niche usually restraining C. albicans in the commensal state to promoting invasive growth, leading to systemic dissemination. Our findings reveal a mechanism underlying a significant risk factor for C. albicans infection, which could inform clinicians regarding future antibiotic selection to minimize this deadly disease incidence.
Highlights
The commensal fungus Candida albicans often causes life-threatening infections in patients who are immunocompromised with high mortality
To determine whether treating bacteria with β-lactam antibiotics affects C. albicans growth state in vitro, we grew C. albicans on plates side by side with several common commensal bacteria, including Gram-positive Staphylococcus aureus (Sa), Staphylococcus epidermidis (Se), and Streptococcus pyogenes (Sp) and Gramnegative Escherichia coli (Ec) and Pseudomonas aeruginosa (Pa)
More than 90% of C. albicans yeast cells switched to hyphal growth upon incubation with β-lactam-treated bacterial culture supernatants, whereas
Summary
The commensal fungus Candida albicans often causes life-threatening infections in patients who are immunocompromised with high mortality. A generally accepted explanation for the correlation between the use of antibiotics and invasive candidiasis is that the killing of commensal bacteria by antibiotics removes competitors, exposes adhesion sites on host epithelial tissues and frees up niches and resources to favour robust fungal proliferation and stable colonization, resulting in higher chances of fungal dissemination from the gastrointestinal lumen to visceral organs[15,18,19]. This explanation fails to reconcile with recent findings that the depletion of bacteria in the gut does not promote the invasive growth of C. albicans. There is increasing evidence indicating that the gastrointestinal tract depleted of bacteria by antibiotics strongly selects C. albicans mutants defective for hyphal growth[6,22]
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