Deficiency of 5-Lipoxygenase Promotes Early Systemic Dissemination of Cryptococcus gattii

Cryptococcosis is a systemic mycosis that affects 1 million people annually, with cryptococcal meningitis representing its most severe manifestation. The main etiological agents are C. neoformans and C. gattii, recognized as priority fungal pathogens. Alveolar macrophages play a central role in the pulmonary immune response, as the lungs are the primary site of infection, and these cells are producers of lipid mediators during inflammatory responses. The enzyme 5-lipoxygenase (5-LOX) is a key component of the leukotriene biosynthetic pathway and plays an important role in inflammation. However, its immunomodulatory role during Cryptococcus infection remains poorly understood. Therefore, this study aimed to investigate the impact of 5-LOX deficiency on the immune response during C. gattii infection. SV129 wild-type (WT) and 5-LOX-deficient (5-LO⁻/⁻) mice were intratracheally inoculated with C. gattii R265. Fungal burden was assessed by quantifying colony-forming units (CFUs) at 4 and 8 days post-infection (dpi), and survival was monitored. Preliminary results showed that 5-LO⁻/⁻ mice exhibited a higher pulmonary fungal burden at 4 dpi than WT mice. At 8 dpi, however, pulmonary fungal burden in 5-LO⁻/⁻ mice remained stable, with no significant increase over time. In contrast, WT mice showed progressive fungal dissemination to the brain and eyes, providing evidence of systemic dissemination during the acute phase. Survival analysis revealed distinct outcomes: WT mice had a median survival of 35 dpi, whereas 5-LO⁻/⁻ mice showed increased resistance, with survival extending to 50 dpi. Overall, these findings suggest that 5-LO deficiency alters the host response to C. gattii infection, resulting in distinct patterns of fungal control and disease progression compared with WT mice. Further studies are warranted to elucidate the cellular and molecular mechanisms underlying the role of the 5-LOX pathway in the immunopathogenesis of cryptococcosis. CEUA: A17/26-A51-24-092-21