Single-cell RNA sequencing unravels T cell exhaustion underlying the chronicity of chromoblastomycosis

Introduction Chromoblastomycosis (CBM) is a chronic, neglected tropical fungal infection. Its immunopathogenesis, particularly the mechanism underlying its chronicity, remains poorly understood. Methods We performed single-cell RNA sequencing (scRNA-seq) on lesional skin from a CBM patient, followed by comprehensive bioinformatics analyses. We then used multiplex immunofluorescence (mIF) to validate CD4 + T cell exhaustion in CBM patient lesions and the mouse model of Fonsecaea pedrosoi infection. Results We identified a significantly expanded population of exhausted CD4 + T cells within the patient’s lesions, which exhibited high co-expression of inhibitory receptors (PD-1, TIM-3, LAG-3) and functional impairment. Trajectory inference suggested a differentiation path from naive towards exhaustion within the chronic inflammatory environment. Cell-cell communication analysis implicated monocytes/macrophages (MoMacs) as key drivers of this process via persistent antigen presentation and ligand-receptor interactions such as CTLA4-CD80/86 and LGALS9-CD44. The accumulation of exhausted CD4 + T cells was confirmed in human CBM lesions by multiplex immunofluorescence (mIF), and the progressive development of exhaustion was recapitulated in the mouse model of Fonsecaea pedrosoi infection. Discussion Our findings establish CD4 + T cell exhaustion as an important mechanism underlying the chronicity of chromoblastomycosis, revealing a new immunopathological perspective for this neglected disease.