Phenotypic immunological profiling and antifungal susceptibility of <i>Sporothrix schenckii</i> clinical isolates from a hyperendemic region in western Mexico

Sporothrix schenckii is the most prevalent etiological agent of sporotrichosis in Mexico, a neglected subcutaneous mycosis with hyperendemic foci in mountainous regions. Despite its public health importance, the phenotypic and virulence-related features of clinical isolates circulating in these areas remain poorly characterized. Ten clinical isolates were molecularly identified and assessed for virulence by determining enzymatic activity (proteases, lipases, catalase), biofilm formation, adhesion to extracellular matrix proteins, antifungal susceptibility, and cell wall composition. Host interaction was evaluated through cytokine profiling in human peripheral blood mononuclear cells, and virulence was assessed using the Galleria mellonella invertebrate infection model. All isolates were confirmed as S. schenckii. Compared to a reference strain, a subset of isolates (740, 742, 183, and 1798) displayed reduced adhesion, extracellular enzymatic activity, and catalase production, as well as altered mannose and rhamnose cell wall content. These isolates induced significantly lower TNFα and higher IL-10 levels in PBMCs and were markedly less virulent in G. mellonella, exhibiting lower mortality, cytotoxicity, and immune activation. All isolates were biofilm producers, and some showed reduced susceptibility to itraconazole or fluconazole. This study reveals phenotypic diversity among S. schenckii clinical isolates in a Mexican hyperendemic region and identifies a subgroup with reduced virulence and immune stimulation capacity. These findings enhance our understanding of the host-pathogen dynamics of sporotrichosis and may inform future diagnostic and therapeutic strategies in endemic settings.