Abstract
PURPOSE: Dematiaceous fungi, such as Phialophora verrucosa (P. verrucosa), cause persistent infections that are difficult to treat. The purpose of this study was to investigate the roles of chemokines CXCL1 and CXCL2 in the innate immune defense against P. verrucosa infections. METHODS: A subcutaneous infection model was employed, in which live P. verrucosa conidia were administered into the footpads of wild-type C57BL/6 mice and their Cxcl1 and Cxcl2 knockout (KO) counterparts (equal numbers of male and female mice). The natural course of infection, pathological changes, and immune responses were monitored continuously over four weeks. RESULTS: The current results show that both CXCL1 and CXCL2 deficiencies impair fungal clearance, leading to prolonged infection as evidenced by higher fungal loads and histopathology in Cxcl1/Cxcl2 KO mice at week 4. In Cxcl1 KO mice, increased levels of inflammatory cytokines IFN-γ, G-CSF, and IL-4 were observed, likely compensating for the immunological deficiencies caused by the lack of CXCL1. Conversely, Cxcl2 KO mice exhibited impaired neutrophil infiltration early in infection, accompanied by a significant increase in macrophage infiltration. CONCLUSION: These findings highlight the critical roles of CXCL1 and CXCL2 in mounting an effective immune response against dematiaceous fungi and suggest their potential as therapeutic targets.