# Acidic pH Modulates Cell Wall and Melanization in Paracoccidioides brasiliensis, Affecting Macrophage Interaction

## TL;DR

This study shows how acidic conditions affect the cell wall and immune evasion of the fungus Paracoccidioides brasiliensis, which causes a serious disease in Latin America.

## Contribution

The study reveals that acidic pH induces melanization and cell wall changes in P. brasiliensis, altering its interaction with macrophages and enhancing virulence.

## Key findings

- Acidic pH increases melanin production and upregulates genes in the DHN-melanin pathway in P. brasiliensis.
- Acidic conditions alter cell wall composition, increasing chitin and reducing mannan, which affects cell wall stability.
- Fungal cells grown under acidic pH are less phagocytosed by macrophages and alter cytokine and nitric oxide production.

## Abstract

Paracoccidioides brasiliensis 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 P. brasiliensis 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 P. brasiliensis, 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 DHN-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, P. brasiliensis 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 P. brasiliensis 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.