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.