Ly6C^hi inflammatory monocytes promote susceptibility to Leishmania donovani infection

Ly6C^hi inflammatory monocytes (iMO) are critical for host defense against toxoplasmosis and malaria but their role in leishmaniasis is unclear. In this study, we report a detrimental role of Ly6C^hi iMOs in visceral leishmaniasis (VL) caused by Leishmania donovani. We demonstrate that Ly6C^hi iMOs are continuously recruited into the spleen and liver during L. donovani infection and they are preferential targets for the parasite. Using microarray-based gene expression profiling, we show that Ly6C^hi iMOs isolated from the infected liver and spleen have distinct phenotypic and activation profiles. Furthermore, we demonstrate that blocking the recruitment of Ly6C^hi iMOs into the liver and spleen during L. donovani infection using a CCR2 antagonist reduces the frequency of the pathogenic IFN-γ/IL10 dual producer CD4+ T cells in the spleen and leads to a significant reduction in parasite loads in the liver and spleen. Using STAT1-/- mice we show that STAT1 is critical for mediating the recruitment of Ly6C^hi iMOs into organs during L. donovani infection, and adaptive transfer of wild type Ly6C^hi iMOs into STAT1-/- recipients renders them susceptible to disease. Our findings reveal an unexpected pathogenic role for Ly6C^hi iMOs in promoting parasite survival in VL and open the possibility of targeting this population for host-directed therapy during VL.