| Summary: | Immunization with various <i>Leishmania</i> species lacking <i>centrin</i> induces robust immunity against a homologous and heterologous virulent challenge, making <i>centrin</i> mutants a putative candidate for a leishmaniasis vaccine. Centrin is a calcium-binding cytoskeletal protein involved in centrosome duplication in higher eukaryotes and <i>Leishmania</i> spp. lacking centrin are unable to replicate <i>in vivo</i> and are non-pathogenic. We developed a <i>centrin</i>-deficient <i>Leishmania braziliensis</i> (<i>LbCen<sup>−/−</sup></i>) cell line and confirmed its impaired survival following phagocytosis by macrophages. Upon experimental inoculation into BALB/c mice, <i>LbCen<sup>−/−</sup></i> failed to induce lesions and parasites were rapidly eliminated. The immune response following inoculation with <i>LbCen<sup>−/−</sup></i> was characterized by a mixed IFN-γ, IL-4, and IL-10 response and did not confer protection against <i>L. braziliensis</i> infection, distinct from <i>L. major</i>, <i>L. donovani</i>, and <i>L mexicana</i> centrin-deficient mutants. A prime-boost strategy also did not lead to a protective immune response against homologous challenge. On the contrary, immunization with <i>centrin</i>-deficient <i>L. donovani</i> (<i>LdonCen<sup>−/−</sup></i>) cross-protected against <i>L. braziliensis</i> challenge, illustrating the ability of <i>LdonCen<sup>−/−</sup></i> to induce the Th1-dominant protective immunity needed for leishmaniasis control. In conclusion, while <i>centrin</i> deficiency in <i>L. braziliensis</i> causes attenuation of virulence, and disrupts the ability to cause disease, it fails to stimulate a protective immune response.
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