P2X7 receptor blockade during Cryptococcus neoformans infection promotes a Th2-associated immune profile and enhances fungal dissemination to the brain.

Cryptococcosis is a systemic fungal infection caused by Cryptococcus species, predominantly Cryptococcus neoformans. The disease affects the lungs and can disseminate to the Central Nervous System (CNS), leading to high-mortality meningoencephalitis. Purinergic signaling, driven by extracellular nucleotides and nucleosides, plays a key role in immune regulation. Among purinergic receptors, P2X7 receptors modulate immune cell activity and cytokine release. However, its role in cryptococcosis remains unclear. Here, we evaluated the effects of Brilliant Blue G (BBG, 50 mg/kg), a widely used pharmacological inhibitor of P2X7 receptor, in a murine model of cryptococcosis. Infection increased pulmonary expression of P2X7, P2Y2, and P2Y12 receptors while reducing A2B receptor levels. Although BBG treatment improved lung mechanics and reduced pulmonary inflammation at 7 days post-infection, it paradoxically resulted in increased mortality. Lung cytokine profiling revealed decreased expression of pro-inflammatory mediators (IL-1β, TNF-α, and IFN-γ), along with elevated levels of IL-10, TGF-β, IL-5, and IL-13, and increased expression of the transcription factors GATA3 and Foxp3, suggesting an association with a Th2/Treg-like immune profile. While pulmonary fungal burden remained unchanged, BBG treatment facilitated fungal dissemination to the brain, accompanied by increased glial activation. These findings suggest that BBG administration is associated with reduced lung inflammation, along with impaired systemic host responses and increased CNS dissemination, highlighting that pulmonary immune responses may influence disease progression and dissemination to distal tissues. Our data support the involvement of purinergic signaling in the control of fungal dissemination to the brain, with effects consistent with P2X7 blockade.