Persistent collagen remodeling after prolonged cotrimoxazole treatment in experimental pulmonary paracoccidioidomycosis

Paracoccidioidomycosis (PCM) is a granulomatous fungal infection endemic to Latin America and is frequently associated with long-term pulmonary sequelae, including fibrosis and emphysema. Although antifungal therapy effectively controls infection, pulmonary remodeling may persist, and the temporal relationship between fungal control, immune changes, and collagen deposition remains incompletely understood. Here, we characterized recoverable fungal burden, pulmonary collagen remodeling, and selected local and systemic immune parameters during prolonged cotrimoxazole (CMX) treatment in experimental PCM. BALB/c mice were infected with Paracoccidioides brasiliensis , and CMX treatment was initiated 4 weeks post-infection. Mice were evaluated after 4, 10, and 20 weeks of treatment. Fungal burden, lung histopathology, collagen deposition, and immunohistochemical markers were assessed. Mediator production by BAL-derived macrophage-enriched adherent cells was evaluated by measuring H 2 O 2 and cytokine levels, whereas peripheral blood monocyte subsets and splenic dendritic cell subsets were analyzed by flow cytometry. During the early treatment phase, BAL-derived macrophage-enriched adherent cells from CMX-treated infected mice showed increased H 2 O 2 and TNF-α production under non-stimulated conditions. At week 20, no viable fungi were recovered from lung cultures of CMX-treated mice, and only small residual granulomatous lesions were observed. Nevertheless, collagen deposition remained detectable in the alveolar septa and pulmonary parenchyma, including areas distant from residual granulomas. Persistent changes were also observed in systemic myeloid populations, including increased circulating CD115⁺Ly6C high monocytes and sustained MHC-II expression on myeloid dendritic cells. These findings reveal a clinically relevant pattern in which marked microbiological control during prolonged CMX treatment coexists with persistent pulmonary collagen remodeling and systemic myeloid alterations that recapitulate, in part, features described in patients with the chronic form of PCM. Together, they expand the translational relevance of this established experimental model by integrating microbiological, structural, and immune changes associated with persistent pulmonary sequelae in PCM.