Authors

Discussion

Leishmania (L.) resists macrophage cytolytic activities and exploits these cells as hosts for intracellular proliferation. Chronic infection in humans can be either asymptomatic or symptomatic, causing devastating immuno-pathologies. The host determinants and immune mechanisms underlying this dichotomy are largely unknown, even though pathways controlling the infection could inform on urgently needed, immune-therapeutic interventions. C57BL/6 mice are reported to control L. donovani infection conversely to hamsters that develop progressive and lethal visceral leishmaniasis. Here we assess the role of the macrophage response between these two rodents in defining systemic infection. We first demonstrated by in vitro infection that only hamster but not mouse peritoneal macrophages allow robust proliferation of L. donovani parasites, thus correlating their permissivity with disease outcome. We further investigated the underlying macrophage responses by transcript profiling. Following the establishment and validation of a protocol for the bulk production of hamster bone marrow-derived macrophages (BMDMs) that allowed robust parasite growth, we conducted a comparative RNAseq analysis in hamster and mouse BMDMs to decipher host-specific transcript signatures in response to infection with L. donovani metacyclic-enriched promastigotes. Total mRNA was extracted from BMDMs 24 hours and 3 days after infection and submitted to RNA sequencing. Our analysis revealed rodent-specific expression changes, with hamster and mouse BMDMs respectively showing changes in abundance for 1941 and 511 transcripts (fold change ≥ 1.5, adjusted p-value < 0.05) at 24 hours, and 3320 and 273 transcripts at day 3 post-infection. The transcript profiles correlated with host factors previously linked to permissivity, including increased expression in hamster BMDMs of arginase 1 known to promote parasite infection, and increased expression in mouse BMDMs of NF-kappa B pathway members known to trigger anti-parasitic activities. Our comparative experimental system allowed us to firmly correlate the differences in parasite survival to differences in the rodent macrophage responses, suggesting that the initial parasite-host cell interaction can define the trajectory towards either acute symptomatic or silent chronic L. donovani infection.