Airspace Candida Colonization and Lung Injury (AirCCoLIN)

– ABSTRACT Candida species are frequently detected in lower respiratory tract (LRT) samples from critically ill patients on mechanical ventilation, yet their role in contributing to lung injury remains poorly understood. Traditionally regarded as benign colonizers, emerging evidence now suggests that Candida in the LRT may actively disrupt lung barrier integrity, potentially exacerbating lung injury and impacting clinical outcomes. Our data, along with other studies, demonstrate that high C.albicans abundance is associated with increased inflammation, lung injury markers, and mortality in these patients. Elevated levels of neutrophil elastase and epithelial injury markers in individuals with Candida colonization indicate that Candida may drive acute lung injury by triggering intense neutrophilic inflammation and epithelial disruption. Additionally, in mouse models, we show that intratracheal (i.t.) C.albicans instillation significantly disrupts lung barrier function, with co-exposure to lipopolysaccharide (LPS) amplifying injury—a clinically relevant two-hit model mimicking acute respiratory distress syndrome (ARDS). One plausible mechanism involves the Dectin-1 receptor, which recognizes fungal beta-D-glucan. Genetic variation in Dectin-1 is linked to differential lung injury outcomes, and preliminary data reveal that Dectin-1 knockout mice exhibit reduced neutrophil recruitment and lung damage, highlighting Dectin-1’s potential role in modulating host injury responses. Additionally, C. albicans virulence factors, such as hyphal formation and candidalysin secretion—established mediators of epithelial damage in mucosal candidiasis—induce significant cytotoxicity and barrier disruption in the lung epithelium, particularly in strains that transition to hyphal forms. Our findings suggest that C. albicans promotes lung injury via two principal mechanisms: (1) by escalating neutrophil-mediated lung injury and (2) by direct epithelial barrier disruption driven by fungal virulence factors. The Airspace Candida Colonization and Lung Injury (AirCCoLIN) study addresses these questions by investigating the impact of host susceptibility, Dectin-1 receptor signaling, and C. albicans virulence factors on lung injury across in vitro assays, mouse models, and human LRT specimens. Aim 1 will delineate host factors, particularly susceptibility and Dectin-1 receptor signaling in neutrophils, that contribute to C.albicans-induced lung injury. Aim 2 will focus on pathogen factors, assessing the impact of C. albicans virulence factors on epithelial barrier integrity and neutrophil responses in both in vitro and in vivo models of lung injury. Aim 3 will identify clinical and molecular predictors of lung injury in ventilated patients colonized with C.albicans in the LRT. Successful completion of the AirCCoLIN study will define novel host- pathogen interactions in the setting of acute lung injury and repair, positioning C. albicans as a potential modifiable target for reducing lung injury in critically ill patients with acute respiratory failure. Given C.albicans' designation as a critical priority pathogen by the World Health Organization, this research could inform innovative therapeutic approaches to mitigate lung injury in this vulnerable population. Project Number: 1R01HL176668-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: Georgios Kitsios | Institution: UNIVERSITY OF PITTSBURGH AT PITTSBURGH, PITTSBURGH, PA | Award Amount: $719,195 | Activity Code: R01 | Study Section: Special Emphasis Panel[ZRG1 RCCS-B (81)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01HL17666801A1