Crosstalk of PD-1 signaling with the SIRT1/FOXO-1 axis during the progression of visceral leishmaniasis

Earlier we documented the role of PD-1 pathway in macrophage apoptosis and the down-regulation of this signaling during infection by intra-macrophage parasite Leishmania donovani. But, during late phase of infection, PD-1 expression was significantly increased without activating host cell apoptosis and its inhibition led to markedly decreased parasite survival, along with increased production of TNFα, IL-12, ROS and NO. Increased PD-1 led to inactivation of AKT resulting in nuclear sequestration of FOXO-1. Transfecting infected cells with constitutively active FOXO-1 (CA-FOXO) led to increased cell death thereby suggesting that nuclear FOXO-1 might be inactivated. Infection significantly induced the expression of SIRT1, which inactivated FOXO-1 by deacetylation and its knock down led to increased apoptosis. SIRT1 knockdown also significantly decreased parasite survival along with increased production of TNFα, ROS and NO. Administration of SIRT1 inhibitor, sirtinol (10 mg/kg body weight) in infected mice decreased spleen parasite burden and a synergistic effect was found with PD-1 inhibitor. Collectively, our study showed that Leishmania utilizes SIRT1/FOXO-1 axis for differentially regulating PD-1 signaling and though interconnected, both pathways independently contribute in intracellular parasite survival.