Pre-Exposureto Cyclosporine A Primes <i>Paracoccidioides brasiliensis</i> to Evade Host Immunity

Abstract Paracoccidioidomycosis (PCM) is a systemic mycosis endemic to South America caused by thermodimorphic fungi of the genus Paracoccidioides, particularly P. brasiliensis. Calcineurin inhibition by cyclosporine A (CsA) perturbs fungal thermodimorphism and growth. Here, we asked whether pre-exposure of P. brasiliensis yeasts to CsA modulates host–pathogen interactions during infection. Mice infected with CsA-pre-exposed fungi exhibited significantly reduced levels of pro- and anti-inflammatory cytokines, along with decreased recruitment and activation of innate and adaptive immune cells at both time points. Although tissue inflammation and lesion areas were diminished, fungal burdens in lungs and liver were similar between groups. Importantly, yeasts recovered from lungs 72 h after infection with CsA-pretreated fungi displayed reduced in vitro colony growth, suggesting that prior CsA exposure induces a persistent slow-growth physiological state. This altered phenotype may impair effective immune recognition and inflammatory activation. As host immunosuppression was excluded in the experimental design, fungus-intrinsic phenotypes consistent with transient calcineurin pathway inhibition: altered growth/morphogenesis and putatively modified PAMP exposure that together blunt early immune activation. We interpret late-phase differences as downstream of these early pathway-dependent shifts rather than as heritable reprogramming. Overall, pre-exposure to CsA modulates P. brasiliensis–host interaction, dissociating tissue injury from fungal burden, highlights the role of calcineurin in fungal adaptation, and demonstrates how environmental exposure to bioactive compounds can influence fungal virulence and disease outcomes.