Host adenosine deaminase reprograms purinergic immunoregulation in Leishmania braziliensis infection

Cutaneous leishmaniasis (CL) caused by Leishmania braziliensis is characterized by intense inflammation that contributes both to parasite control and tissue pathology. Purinergic signalling, particularly mediated by adenosine and its receptors, has been implicated in immune modulation during Leishmania infection, yet its functional relevance in L. braziliensis remains poorly defined. Here, we investigated the roles of adenosine A2A and A2B receptors and adenosine deaminase (ADA) in regulating immune responses during L. braziliensis infection. Transcriptomic analyses of human CL lesions revealed increased expression of ADORA2A , which paradoxically correlated positively with pro-inflammatory and microbicidal gene signatures. Despite modulating the receptor expression on L. braziliensis -infected macrophages as well, pharmacological inhibition of A2A or A2B receptors did not affect parasite burden, reactive oxygen species (ROS) production, or inflammatory cytokine release. Thus suggesting that adenosine receptor signalling is dispensable in this context. In contrast, ADA and ADA2 were markedly upregulated in CL lesions and infected macrophages and showed strong positive correlations with inflammatory mediators. Functional inhibition of ADA with pentostatin significantly increased intracellular parasite load and reduced ROS, TNF-α, and IL-1β production, demonstrating a critical role for ADA in sustaining macrophage microbicidal activity. These findings suggest that ADA activity is central to modulating adenosine-mediated immunosuppression in CL and may serve as both a biomarker of disease activity and a potential therapeutic target. • ADORA2A is elevated in CL lesions and associates with pro-inflammatory signatures. • A2AR blockade does not affect L. braziliensis control by macrophages. • ADA is strongly upregulated in L. braziliensis lesions and macrophages. • ADA expression correlates with inflammatory mediators in L. braziliensis infection. • ADA inhibition increases L. braziliensis burden and impairs microbicidal responses.