Mariana Araujo Oliveira, Ywa Perpétuo Socorro Toda Tavares, Renata Chaves Albuquerque, Silene Migliorini, Sandro Rogério Almeida, Joilson O Martins
Diabetic mice exhibited enhanced susceptibility to infection compared to normoglycemic controls, presenting with progressive ulcerative lesions, systemic dissemination (lymph nodes, liver, and brain), and 100% mortality. This severe phenotype was accompanied by a dysregulated inflammatory profile, characterized by elevated systemic TNF-α, IFN-γ, and IL-6 alongside reduced splenic CD4+ T cell frequencies. Functionally, macrophages from diabetic hosts displayed an initial increase in yeast association followed by a rapid decline, consistent with cellular exhaustion. Additionally, infected diabetic mice exhibited hepatic accumulation of p62/SQSTM1 without alterations in Beclin-1 or LC3B-II, suggesting potential disruption during late-stage autophagic clearance.
INTRODUCTION: This study establishes and characterizes a novel experimental mouse model to evaluate Sporothrix brasiliensis infection under type 1 diabetic conditions, providing a comprehensive description of the associated clinicopathological and immunometabolic alterations.
METHODS: Diabetic and normoglycemic control mice were infected with S. brasiliensis to evaluate clinical progression, fungal dissemination, mortality, systemic cytokines, splenic T cell subsets, macrophage functional responses, and hepatic autophagic markers (p62/SQSTM1, Beclin-1, and LC3B-II).
RESULTS: Diabetic mice exhibited enhanced susceptibility to infection compared to normoglycemic controls, presenting with progressive ulcerative lesions, systemic dissemination (lymph nodes, liver, and brain), and 100% mortality. This severe phenotype was accompanied by a dysregulated inflammatory profile, characterized by elevated systemic TNF-α, IFN-γ, and IL-6 alongside reduced splenic CD4+ T cell frequencies. Functionally, macrophages from diabetic hosts displayed an initial increase in yeast association followed by a rapid decline, consistent with cellular exhaustion. Additionally, infected diabetic mice exhibited hepatic accumulation of p62/SQSTM1 without alterations in Beclin-1 or LC3B-II, suggesting potential disruption during late-stage autophagic clearance.
DISCUSSION: Overall, this model successfully reproduces severe, disseminated sporotrichosis under hyperglycemic conditions and delineates the multifaceted immune dysregulation associated with host susceptibility. This novel experimental platform provides a valuable tool for future studies exploring fungal pathogenesis and therapeutic strategies in metabolic comorbidities.