Centrin-deficient Leishmania mexicana confers protection against Old World visceral leishmaniasis
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. Vaccina...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2022-12-01
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| Series: | npj Vaccines |
| Online Access: | https://doi.org/10.1038/s41541-022-00574-x |
| _version_ | 1827615423995052032 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Subir Karmakar |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-09T09:10:44Z |
| format | Article |
| id | doaj.art-26413e213d76441788ba0d0d2b589f6a |
| institution | Directory Open Access Journal |
| issn | 2059-0105 |
| language | English |
| last_indexed | 2024-03-09T09:10:44Z |
| publishDate | 2022-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Vaccines |
| spelling | doaj.art-26413e213d76441788ba0d0d2b589f6a2023-12-02T08:31:35ZengNature Portfolionpj Vaccines2059-01052022-12-01711910.1038/s41541-022-00574-xCentrin-deficient Leishmania mexicana confers protection against Old World visceral leishmaniasisSubir Karmakar0Greta Volpedo1Wen-Wei Zhang2Patrick Lypaczewski3Nevien Ismail4Fabiano Oliveira5James Oristian6Claudio Meneses7Sreenivas Gannavaram8Shaden Kamhawi9Shinjiro Hamano10Jesus G. Valenzuela11Greg Matlashewski12Abhay R. Satoskar13Ranadhir Dey14Hira L. Nakhasi15Divsion of Emerging and Transfusion Transmitted Diseases, CBER, FDADepartment of Pathology and Microbiology, Ohio State UniversityDepartment of Microbiology and Immunology, McGill UniversityDepartment of Microbiology and Immunology, McGill UniversityDivsion of Emerging and Transfusion Transmitted Diseases, CBER, FDAVector Molecular Biology Section, Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, NIHVector Molecular Biology Section, Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, NIHVector Molecular Biology Section, Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, NIHDivsion of Emerging and Transfusion Transmitted Diseases, CBER, FDAVector Molecular Biology Section, Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, NIHDepartment of Parasitology, Institute of Tropical Medicine (NEKKEN), Nagasaki UniversityVector Molecular Biology Section, Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, NIHDepartment of Microbiology and Immunology, McGill UniversityDepartment of Pathology and Microbiology, Ohio State UniversityDivsion of Emerging and Transfusion Transmitted Diseases, CBER, FDADivsion of Emerging and Transfusion Transmitted Diseases, CBER, FDAAbstract 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.https://doi.org/10.1038/s41541-022-00574-x |
| spellingShingle | 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 Centrin-deficient Leishmania mexicana confers protection against Old World visceral leishmaniasis npj Vaccines |
| title | Centrin-deficient Leishmania mexicana confers protection against Old World visceral leishmaniasis |
| title_full | Centrin-deficient Leishmania mexicana confers protection against Old World visceral leishmaniasis |
| title_fullStr | Centrin-deficient Leishmania mexicana confers protection against Old World visceral leishmaniasis |
| title_full_unstemmed | Centrin-deficient Leishmania mexicana confers protection against Old World visceral leishmaniasis |
| title_short | Centrin-deficient Leishmania mexicana confers protection against Old World visceral leishmaniasis |
| title_sort | centrin deficient leishmania mexicana confers protection against old world visceral leishmaniasis |
| url | https://doi.org/10.1038/s41541-022-00574-x |
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