The recovery of Candida species (spp.) from lower respiratory tract (LRT) secretions in critically ill patients has traditionally been considered benign. However, emerging evidence suggests that Candida in the LRT may be associated with adverse clinical outcomes during mechanical ventilation. To investigate the impact of Candida on lung injury in mice, we performed intratracheal inoculation of C. albicans and assessed for lung barrier function. We found that intratracheal C. albicans potentiated lung barrier disruption by lipopolysaccharide. Furthermore, intratracheal C. albicans alone was sufficient to induce lung injury, marked by neutrophil airspace recruitment and barrier disruption. Intratracheal C. albicans exposure in neutrophil depleted mice (PMNDTR) exacerbated lung injury and led to fungal dissemination. In lung epithelial cell culture, C. albicans caused significant lung epithelial cytotoxicity, which was attenuated with heat-killed and yeast-locked (TNRG1) C. albicans strains. Human data corroborated our murine model findings, demonstrating elevated biomarkers of epithelial lung injury and worse lung injury endpoints among patients with LRT Candida spp. Our study challenges the dogma that LRT Candida is harmless, suggesting that C. albicans can both directly cause lung injury and exacerbate lung injury from other insults. Elucidating these host-pathogen interactions may uncover new therapeutic targets in the management of acute respiratory failure in critically ill patients.

Dr. Kitsios has received research funding from Genentech, Inc and Pfizer, Inc, unrelated to this work. Dr. Morris has received research funding from Pfizer, Inc, unrelated to this work. The other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Dr. Kitsios: University of Pittsburgh Department of Medicine KARAT Award; NIH (R03 HL162655), American Lung Association COVID-19 Respiratory Virus Research; UPMC Competitive Medical Research Fund Award; Dr. Bain: Career Development Award Number IK2 BX004886 from the United States Department of Veterans Affairs Biomedical Laboratory R&D (BLRD) Service

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