Physiological Disruption of Epithelial Barrier Integrity by Pathogenic Fungi and Its Systemic Implications

Epithelial barriers of the skin, gastrointestinal tract, respiratory tract, and urogenital surfaces provide the first line of defense against pathogenic invasion while supporting diverse commensal microbiota. These barriers rely on tight and adherent junctions, mucosal secretions, and immune surveillance to maintain integrity. Pathogenic fungi overcome these defenses by employing virulence strategies such as adhesion through specialized surface proteins, morphological transitions, biofilm formation, secretion of hydrolytic enzymes, and release of toxins, including the Candida albicans peptide candidalysin. These processes compromise junctional complexes, disrupt epithelial polarity, and trigger inflammatory responses, resulting in increased permeability and barrier dysfunction. While many fungal infections remain superficial, opportunistic pathogens such as C. albicans, Aspergillus fumigatus, and Cryptococcus neoformans can breach epithelial barriers, disseminate systemically, and cause life-threatening disease, particularly in immunocompromised individuals. Host epithelial and immune cells respond to fungal invasion through pattern recognition receptors, cytokine release, and recruitment of phagocytes, yet fungal immune evasion frequently undermines clearance. Understanding the molecular mechanisms of fungal-epithelial interactions and systemic dissemination provides critical insights for developing targeted therapies that preserve barrier function and strengthen antifungal immunity.