Centrin-deficient Leishmania mexicana confers protection against Old World visceral leishmaniasis

Leishmaniasis is one of the top neglected tropical diseases with significant morbidity and mortality in low and middle-income countries (LMIC). However, this disease is also spreading in the developed world. Currently, there is a lack of effective strategies to control this disease. Vaccination can be an effective measure to control leishmaniasis and has the potential to achieve disease elimination. Recently, we have generatedcentringene-deleted new worldL. mexicana(LmexCen−/−) parasites using CRISPR/Cas9 and showed that they protect mice against a homologousL. mexicanainfection that causes cutaneous disease. In this study, we tested whetherLmexCen−/−parasites can also protect against visceral leishmaniasis caused byL. donovaniin a hamster model. We showed that immunization withLmexCen−/−parasites is safe and does not cause lesions. Furthermore, such immunization conferred protection against visceral leishmaniasis caused by a needle-initiatedL. donovanichallenge, as indicated by a significant reduction in the parasite burdens in the spleen and liver as well as reduced mortality. Similar control of parasite burden was also observed against a sand fly mediatedL. donovanichallenge. Importantly, immunization withLmexCen−/−down-regulated the disease promoting cytokines IL-10 and IL-4 and increased pro-inflammatory cytokine IFN-γ resulting in higher IFN-γ/IL-10 and IFN-γ/IL4 ratios compared to non-immunized animals.LmexCen−/−immunization also resulted in long-lasting protection againstL. donovaniinfection. Taken together, our study demonstrates that immunization withLmexCen−/−parasites is safe and efficacious against the Old World visceral leishmaniasis.