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

Karmakar, S.; Volpedo, G.; Zhang, W.-W.; Lypaczewski, P.; Ismail, N.; Oliveira, L. F.; Oristian, J.; Meneses, C.; Gannavaram, S.; Kamhawi, S.; Hamano, S.; Valenzuela, J. G.; DEY, R.; Satoskar, A. R.; Matlashewski, G.; Nakhasi, H.

doi:10.1101/2022.06.27.497754

bioRxiv · 10.1101/2022.06.27.497754

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

Karmakar, S.·Volpedo, G.·Zhang, W.-W.·Lypaczewski, P.·Ismail, N.·Oliveira, L. F.·Oristian, J.·Meneses, C.·Gannavaram, S.·Kamhawi, S.·Hamano, S.·Valenzuela, J. G.·DEY, R.·Satoskar, A. R.·Matlashewski, G.·Nakhasi, H.

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Abstract

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 generated centrin gene-deleted new world L. mexicana (LmexCen-/-) parasites using CRISPR/Cas9 and showed that they protect mice against a homologous L. mexicana infection that causes cutaneous disease. In this study, we tested whether LmexCen-/- parasites can also protect against visceral leishmaniasis caused by L. donovani in a hamster model. We show that immunization with LmexCen-/- parasites is safe and does not cause lesions. Furthermore, such immunization conferred protection against visceral leishmaniasis caused by a needle-initiated L. donovani challenge, as indicated by a significant reduction in the parasite burdens in the spleen and liver and lack of mortality. Similar control of parasite burden was also observed against a sand fly mediated L. donovani challenge. Importantly, immunization with LmexCen-/- down-regulated the Th2 response as indicated by a significant reduction in the anti-inflammatory cytokines such as IL-10 and IL-4 and increased pro-inflammatory cytokine IFN-{gamma} resulting in higher IFN-{gamma}/IL-10 and IFN-{gamma}/IL4 ratios compared to non-immunized animals. This contrasts with our studies with L. major centrin deletion mutants that showed a dominant Th1 response compared to L. major wild-type infection suggesting the divergent mechanisms of protection in the two mutant parasites. LmexCen-/- immunization resulted in long-lasting protection against L. donovani infection. Further, since the efficacy of LmCen-/- has not been determined against Leishmania strains prevalent in the Americas, LmexCen-/- may be a viable alternative. Taken together, our study demonstrates that immunization with LmexCen-/- parasites is safe and efficacious against old world visceral leishmaniasis.

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Karmakar, S., Volpedo, G., Zhang, W.-W., Lypaczewski, P., Ismail, N., Oliveira, L. F., Oristian, J., Meneses, C., Gannavaram, S., Kamhawi, S., Hamano, S., Valenzuela, J. G., DEY, R., Satoskar, A. R., Matlashewski, G., Nakhasi, H.. 2022-06-29. Centrin-deficient Leishmania mexicana confers protection against Old World visceral leishmaniasis. https://doi.org/10.1101/2022.06.27.497754

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