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Immunization with centrin-Deficient Leishmania braziliensis Does Not Protect against Homologous Challenge
Francys Avendaño-Rangel1,2, Gabriela Agra-Duarte1, Pedro B Borba1
1Instituto Gonçalo Moniz, FIOCRUZ, Salvador 40296-710, BA, Brazil.
Insights
Centrin-deficient Leishmania braziliensis failed to induce protective immunity against leishmaniasis. However, Leishmania donovani centrin mutants showed cross-protection, highlighting their vaccine potential for leishmaniasis control.
Area of Science:
- Parasitology
- Immunology
- Vaccine Development
Background:
- Centrin is a crucial protein for Leishmania replication and pathogenicity.
- Centrin-deficient Leishmania mutants are non-pathogenic and unable to replicate in vivo.
- Previous studies suggest centrin mutants of some Leishmania species are promising vaccine candidates.
Purpose of the Study:
- To investigate the immunogenicity and protective potential of a centrin-deficient Leishmania braziliensis (LbCen) mutant.
- To evaluate the immune response elicited by LbCen in a mouse model.
- To compare the efficacy of LbCen with other centrin-deficient Leishmania species for leishmaniasis vaccine development.
Main Methods:
- Development of a centrin-deficient Leishmania braziliensis (LbCen) cell line.
- Assessment of LbCen survival within macrophages.
- Experimental inoculation of LbCen into BALB/c mice to evaluate lesion development and parasite clearance.
- Characterization of the immune response (IFN-γ, IL-4, IL-10) following LbCen inoculation.
- Evaluation of a prime-boost immunization strategy with LbCen.
- Assessment of cross-protection against Leishmania braziliensis challenge using a centrin-deficient Leishmania donovani (LdonCen) mutant.
Main Results:
- LbCen exhibited impaired survival after phagocytosis by macrophages.
- Inoculation of LbCen into mice did not induce lesions and parasites were rapidly cleared.
- The immune response to LbCen was characterized by mixed IFN-γ, IL-4, and IL-10 levels, and did not confer protection against L. braziliensis.
- A prime-boost strategy with LbCen also failed to induce protective immunity.
- Immunization with LdonCen conferred cross-protection against L. braziliensis challenge, indicating Th1-dominant immunity.
Conclusions:
- Centrin deficiency in Leishmania braziliensis attenuates virulence but does not stimulate a protective immune response.
- Leishmania donovani centrin-deficient mutants induce protective immunity and cross-protection against Leishmania braziliensis.
- LdonCen holds potential as a vaccine candidate for leishmaniasis control, unlike LbCen.
Abstract:
Immunization with various Leishmania species lacking centrin induces robust immunity against a homologous and heterologous virulent challenge, making centrin mutants a putative candidate for a leishmaniasis vaccine. Centrin is a calcium-binding cytoskeletal protein involved in centrosome duplication in higher eukaryotes and Leishmania spp. lacking centrin are unable to replicate in vivo and are non-pathogenic. We developed a centrin-deficient Leishmania braziliensis (LbCen) cell line and confirmed its impaired survival following phagocytosis by macrophages. Upon experimental inoculation into BALB/c mice, LbCen failed to induce lesions and parasites were rapidly eliminated. The immune response following inoculation with LbCen was characterized by a mixed IFN-γ, IL-4, and IL-10 response and did not confer protection against L. braziliensis infection, distinct from L. major, L. donovani, and L mexicana centrin-deficient mutants. A prime-boost strategy also did not lead to a protective immune response against homologous challenge. On the contrary, immunization with centrin-deficient L. donovani (LdonCen) cross-protected against L. braziliensis challenge, illustrating the ability of LdonCen to induce the Th1-dominant protective immunity needed for leishmaniasis control. In conclusion, while centrin deficiency in L. braziliensis causes attenuation of virulence, and disrupts the ability to cause disease, it fails to stimulate a protective immune response.
