Increased host ATP efflux and its conversion to extracellular adenosine is crucial for establishing Leishmania infection

Abstract

Intracellular survival of Leishmania donovani demands rapid production of host ATP for its sustenance. However, gradual decrease in intracellular ATP in spite of increased glycolysis suggested ATP efflux during infection. Accordingly, extracellular ATP showed an increase and pannexin-1 was found to be the major ATP exporter in infected condition. Extracellular ATP also showed a gradual decrease after initial increase and analysing cell surface ATP-degrading enzymes revealed induction of the ectonucleotidases, CD39 and CD73. Ectonucleotidase mediated ATP degradation led to increased extracellular adenosine (eADO) and inhibiting CD39 and CD73 in infected cells decreased adenosine concentration and parasite survival, documenting importance of adenosine in infection. Inhibiting adenosine uptake by cells did not affect parasite survival implicating eADO might exert its effect through receptor-mediated signaling. Leishmania indeed induced expression of adenosine receptors A2AR and A2BR, both being important for anti-inflammatory responses. Treating infected BALB/c mice with CD39 and CD73 inhibitors resulted in decreased parasite burden and increased host-favourable cytokine production. Collectively, these observations indicate that infection-induced ATP is exported and after converting into adenosine exerts receptor-mediated signaling for propagating infection.