Centrin-deficient Leishmania mexicana as a safe and effective vaccine against cutaneous leishmaniasis
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Date
2019-03
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Abstract
Leishmaniasis is a neglected protozoan disease affecting over 12 million people in more than 90 tropical and subtropical countries. Despite the high morbidity and mortality of this condition, there are no approved vaccines for human use. Using the CRISPR/Cas9 technique, our group has generated live attenuated Centrin knock out (Cen-/-) Leishmania parasites. Centrin is a cytoskeletal protein important for cellular division in eukaryotes and, in Leishmania, it is only necessary for amastigote replication. Our data shows that Leishmania (L.) mexicana Cen-/- amastigotes present a growth defect, which results in significantly lower survival within murine bone marrow-derived macrophages and dendritic cells and in the augmented production of the protective cytokine interleukin (IL)-12, compared to the wild type (WT) strain. In vivo, we confirmed that L. mexicana Cen-/- parasites are safe in a susceptible murine model and do not lead to clinical symptoms. Vaccinated mice produced higher ratios of protective cytokines, such as interferon (IFN)-γ, vs. disease exacerbating cytokines, such as IL-10 and IL-4, compared to the group infected with L. mexicana WT. Additionally, centrin deficient L. mexicana and L. major, another CL strain, live attenuated parasites are effective in the protection against L. mexicana WT challenge, as they elicit a protective immune response while ameliorating, if not obliterating, the clinical symptoms of CL. Taken all together these results suggest that live attenuated Cen-/- parasites are effective candidate prophylactic vaccines for protection and cross-protection against CL.
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Biological Sciences: 1st Place (The Ohio State University Edward F. Hayes Graduate Research Forum)
Keywords
Cutaneous leishmaniasis, live attenuated vaccine
Citation
Published version: Volpedo, G., Pacheco-Fernandez, T., Holcomb, E.A. et al. Centrin-deficient Leishmania mexicana confers protection against New World cutaneous leishmaniasis. npj Vaccines 7, 32 (2022). https://doi.org/10.1038/s41541-022-00449-1