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

Subir Karmakar; Greta Volpedo; Wen-Wei Zhang; Patrick Lypaczewski; Nevien Ismail; Fabiano Oliveira; James Oristian; Claudio Meneses; Sreenivas Gannavaram; Shaden Kamhawi; Shinjiro Hamano; Jesus G Valenzuela; Greg Matlashewski; Abhay R Satoskar; Ranadhir Dey; Hira L Nakhasi

doi:10.1038/s41541-022-00574-x

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

NPJ Vaccines. 2022 Dec 3;7(1):157. doi: 10.1038/s41541-022-00574-x.

Authors

Subir Karmakar¹, Greta Volpedo², Wen-Wei Zhang³, Patrick Lypaczewski³, Nevien Ismail¹, Fabiano Oliveira⁴, James Oristian⁴, Claudio Meneses⁴, Sreenivas Gannavaram¹, Shaden Kamhawi⁵, Shinjiro Hamano^{6

7}, Jesus G Valenzuela⁸, Greg Matlashewski⁹, Abhay R Satoskar¹⁰, Ranadhir Dey¹¹, Hira L Nakhasi¹²

Affiliations

¹ Divsion of Emerging and Transfusion Transmitted Diseases, CBER, FDA, Silver Spring, MD, USA.
² Department of Pathology and Microbiology, Ohio State University, Columbus, OH, USA.
³ Department of Microbiology and Immunology, McGill University, Montreal, QC, Canada.
⁴ Vector Molecular Biology Section, Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, NIH, Rockville, MD, 20852, USA.
⁵ Vector Molecular Biology Section, Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, NIH, Rockville, MD, 20852, USA. skamhawi@niaid.nih.gov.
⁶ Department of Parasitology, Institute of Tropical Medicine (NEKKEN), Nagasaki University, Nagasaki, Japan.
⁷ The Joint Usage/Research Center on Tropical Disease, Institute of Tropical Medicine (NEKKEN), Nagasaki University, Nagasaki, Japan.
⁸ Vector Molecular Biology Section, Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, NIH, Rockville, MD, 20852, USA. jvalenzuela@niaid.nih.gov.
⁹ Department of Microbiology and Immunology, McGill University, Montreal, QC, Canada. Greg.matlashewski@mcgill.ca.
¹⁰ Department of Pathology and Microbiology, Ohio State University, Columbus, OH, USA. Abhay.Satoskar@osumc.edu.
¹¹ Divsion of Emerging and Transfusion Transmitted Diseases, CBER, FDA, Silver Spring, MD, USA. Ranadhir.Dey@fda.hhs.gov.
¹² Divsion of Emerging and Transfusion Transmitted Diseases, CBER, FDA, Silver Spring, MD, USA. Hira.Nakhasi@fda.hhs.gov.

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 showed 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 as well as reduced mortality. Similar control of parasite burden was also observed against a sand fly mediated L. donovani challenge. Importantly, immunization with LmexCen^-/- 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 against L. donovani infection. Taken together, our study demonstrates that immunization with LmexCen^-/- parasites is safe and efficacious against the Old World visceral leishmaniasis.