Research ArticleInfectious Disease

Identification of broadly conserved cross-species protective Leishmania antigen and its responding CD4+ T cells

Science Translational Medicine  21 Oct 2015:
Vol. 7, Issue 310, pp. 310ra167
DOI: 10.1126/scitranslmed.aac5477

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Committing Leishmania vaccine to memory

Leishmaniasis is a potentially fatal disease caused by a protozoal parasite transmitted through sand fly bites. There is currently no vaccine, but affected individuals are resistant to further infection, suggesting vaccination is possible. Now, Mou et al. have found that vaccination with an immunodominant antigen—phosphoenolpyruvate carboxykinase (PEPCK)—protects against leishmaniasis. The authors identified PEPCK by examining peptides that could elicit memory T cell responses from healed but not uninfected animals. PEPCK was conserved in all pathogenic Leishmania and induced immune responses in both infected mice and human cells. Protection in mice was effective across species and was durable, supporting testing of a PEPCK-based vaccine in humans.

Abstract

There is currently no clinically effective vaccine against leishmaniasis because of poor understanding of the antigens that elicit dominant T cell immunity. Using proteomics and cellular immunology, we identified a dominant naturally processed peptide (PEPCK335–351) derived from Leishmania glycosomal phosphoenolpyruvate carboxykinase (PEPCK). PEPCK was conserved in all pathogenic Leishmania, expressed in glycosomes of promastigotes and amastigotes, and elicited strong CD4+ T cell responses in infected mice and humans. I-Ab–PEPCK335–351 tetramer identified protective Leishmania-specific CD4+ T cells at a clonal level, which comprised ~20% of all Leishmania-reactive CD4+ T cells at the peak of infection. PEPCK335–351–specific CD4+ T cells were oligoclonal in their T cell receptor usage, produced polyfunctional cytokines (interleukin-2, interferon-γ, and tumor necrosis factor), and underwent expansion, effector activities, contraction, and stable maintenance after lesion resolution. Vaccination with PEPCK peptide, DNA expressing full-length PEPCK, or rPEPCK induced strong durable cross-species protection in both resistant and susceptible mice. The effectiveness and durability of protection in vaccinated mice support the development of a broadly cross-species protective vaccine against different forms of leishmaniasis by targeting PEPCK.

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