Dermatophyte Virulence and Host Immunity: Key Mechanisms and Clinical Implications Original paper

What was reviewed?

This review article provides a comprehensive synthesis of the current understanding of dermatophyte pathogenicity and host immune responses. It covers fungal virulence factors, including keratinolytic enzymes and pH-responsive regulatory proteins, and explores innate and adaptive host defenses. The authors specifically highlight recent findings in the molecular mechanisms of fungal invasion, immune evasion, and drug resistance, as well as the interplay between fungal pathogens and host pattern recognition receptors (PRRs). Key emphasis is placed on the pathophysiology of chronic and deep dermatophytosis, particularly in the context of CARD9 mutations and impaired Th17 responses.

Who was reviewed?

The review aggregates data from a broad range of studies involving both in vitro and in vivo models, as well as clinical case reports and genetic analyses from patients with dermatophytosis. Notably, the authors reference case series involving CARD9-deficient individuals from North Africa and Asia, murine models of Trichophyton and Microsporum infections, and human keratinocyte co-culture systems. These sources allow the authors to connect clinical phenotypes with immunological and molecular insights.

Most important findings

Dermatophyte virulence is driven by enzymatic degradation of keratin via proteases (e.g., Sub3, Mep3, DppIV) and sulfite production (via cysteine dioxygenase and Ssu1), which enables nutrient acquisition from host tissue. Dermatophytes adapt to changing skin pH via the PacC/Pal signaling pathway, enhancing protease expression. The review also underscores the emergence of antifungal resistance, particularly in T. indotineae, mediated by mutations in the SQLE gene and upregulation of ABC transporters and CYP51B.

Host immunity is initiated by PRRs such as Dectin-1, TLR2/4, and NLRP3, which activate signaling cascades involving CARD9 and MALT1, promoting cytokine release (e.g., IL-17, IL-1β, TNF-α). IL-17-mediated (Th17) responses are central in fungal clearance, regulating antimicrobial peptide production (cathelicidin, β-defensins, S100 proteins), neutrophil recruitment, and keratinocyte proliferation. CARD9 deficiency impairs these pathways, particularly Th17 differentiation, predisposing individuals to chronic or deep fungal infections. These deficiencies are geographically clustered and genetically characterized by mutations like p.Q289X and p.R101C.

Key implications

The article delineates how dermatophyte infections persist and become chronic through complex pathogen-host interactions, revealing potential therapeutic targets. Protease inhibitors, ureases and pH modulation strategies, and immunomodulatory interventions aimed at enhancing Th17 responses could be leveraged as adjunctive treatments. Importantly, identifying CARD9 mutations in patients with refractory or deep dermatophytosis offers a genetic diagnostic tool and may guide immunotherapy decisions, such as IL-17 supplementation or JAK inhibition in cases of STAT1 gain-of-function. These insights bridge mycology, immunology, and clinical dermatology, particularly useful for managing treatment-resistant or recurrent cases.