Adenosine/A _2A R/PKA signaling regulates HO-1-mediated anti-inflammatory responses during <i>Leishmania donovani</i> infection

Visceral leishmaniasis, caused by the protozoan parasite <i>Leishmania donovani</i>, is a major health concern affecting over a million people worldwide. An increase in host ATP production and its efflux benefits the survival of Leishmania parasites and prolongs the infection. Effluxed ATP is converted to adenosine, which activates adenosine-A_2AR signaling to provide an immunosuppressive milieu, necessary for infection propagation. This study identified cAMP/PKA as the essential components of A_2AR signaling, which further differentially activate two transcription factors to induce the antioxidant enzyme HO-1, responsible for creating the anti-inflammatory environment. Our findings highlight A_2AR as a promising drug target against visceral leishmaniasis and other inflammation-related diseases, offering us the opportunity to alleviate inflammatory responses, thereby broadening the impact on disease management and therapy.