Oral L-Arginine Treatment Attenuates<i>Cryptococcus neoformans</i>Extrapulmonary Dissemination and Disease Progression

<i>Cryptococcus neoformans</i> is an opportunistic fungal pathogen causing severe infections in immunocompromised individuals. Arginine metabolism is critical for immune regulation, but its precise role in cryptococcal pathogenesis is not well understood. In this study, we investigated systemic and tissue-specific alterations in L-arginine metabolism during pulmonary <i>C. neoformans</i> infection and evaluated L-arginine supplementation as a potential therapy using a murine model. Key assessments included fungal burden quantification, inflammatory cell and cytokine characterization, brain gene expression analysis, histological examinations, and survival studies. We found significant depletion of serum L-arginine and its downstream metabolites, accompanied by increased arginase activity in infected tissues, indicating a disrupted metabolic balance. Gene expression analysis showed distinct metabolic shifts, including upregulation of arginase-1 (Arg1) and proline metabolism genes, with concurrent suppression of nitric oxide synthase 2 (Nos2) in the brain during the late infection phase. Oral L-arginine supplementation significantly reduced fungal burdens in the brain and spleen, suggesting its effectiveness in controlling cryptococcal dissemination from the lungs. Mechanistically, L-arginine promoted protective immune responses within the mouse brain, improved microglial-mediated cryptococcal clearance and reduced cryptococcal invasion across brain endothelial cells. Consequently, L-arginine administration improved survival and clinical scores, alongside decreasing brain cryptococcoma in infected mice. In summary, oral L-arginine treatment alleviates <i>C. neoformans</i> dissemination by augmenting brain's immune response. This study provides crucial insights into arginine metabolism in cryptococcal disease progression, supporting L-arginine as a promising immunomodulatory therapy.