Acidic pH Modulates Cell Wall and Melanization in <i>Paracoccidioides brasiliensis</i>, Affecting Macrophage Interaction

<i>Paracoccidioides brasiliensis</i> is a thermally dimorphic fungal pathogen and the main etiological agent of paracoccidioidomycosis (PCM), a neglected systemic mycosis endemic in Latin America. The virulence of <i>P. brasiliensis</i> is closely associated with its capacity to survive under hostile host conditions, including acidic environments. In this study, we demonstrate that acidic pH induces melanization in <i>P. brasiliensis</i>, modulates its cell wall composition, and alters the interaction with macrophages. Cultivation at acidic pH resulted in reduced fungal growth without compromising viability and triggered increased production of melanin-like pigments, as confirmed by enhanced laccase activity and upregulation of genes in the <i>DHN</i>-melanin biosynthetic pathway. Additionally, growth under acidic pH induced significant remodeling of the fungal cell wall, leading to increased chitin on the cell wall surface and reduced mannan content, while β-glucan levels remained unchanged. These modifications correlated with decreased viability to Congo Red, suggesting altered cell wall stability. Importantly, <i>P. brasiliensis</i> grown under acidic conditions exhibited reduced phagocytosis by RAW 264.7 macrophages, along with changes in nitric oxide and cytokine production, indicating potential mechanisms of immune evasion. Collectively, our findings suggest that environmental acidification promotes fungal adaptations that enhance survival and modulate host–pathogen interactions, contributing to <i>P. brasiliensis</i> virulence. Understanding how acidic pH regulates these processes provides new insights into the pathobiology of PCM and may contribute to understanding the mechanisms of fungal immune evasion.