Candida in the lower respiratory tract induces barrier disruption in mice and predicts poor outcomes in mechanically ventilated humans

Candida albicans ( Calb ) in the lower respiratory tract (LRT) is considered a rare cause of pneumonia, yet its frequent recovery from LRT secretions of mechanically ventilated patients associates with poor clinical outcomes. To determine whether Calb contributes to lung injury, we conducted a translational investigation spanning two independent, prospective human cohorts, murine models of lung injury, and in vitro assays. In critically ill patients, Calb was the most abundant fungus in LRT specimens, and its detection associated with increased markers of lung injury, prolonged mechanical ventilation, and increased mortality. In a murine model, intratracheal Calb was sufficient to disrupt the air-blood barrier and recruit neutrophils, effects markedly attenuated with heat-killed Calb . Neutrophil depletion led to uncontrolled fungal growth, systemic dissemination and mortality, with surviving mice exhibiting worsened barrier disruption, demonstrating that neutrophils support pathogen control while lung injury is driven by the live organism. Calb induced lung epithelial cytotoxicity as well as barrier disruption in human alveolar epithelial cells at air liquid interface. Yeast-locked mutants without hyphal morphogenesis demonstrated attenuated barrier disruption in human alveolar cells and diminished lung injury in mice, despite higher fungal burden. In human cohort data, LRT microbiome profiles with high Calb abundance and codominant bacterial pathogens predicted worse mortality, and mouse models confirmed that Calb amplifies lung barrier disruption when followed by Pseudomonas aeruginosa inoculation, an effect requiring hyphal morphogenesis. These findings establish that LRT Calb causes direct air-blood barrier disruption through hyphal morphogenesis and amplifies bacterial lung injury, challenging the prevailing view of Candida as an innocent respiratory bystander.