RT Journal Article
SR Electronic
T1 Identification of broadly conserved cross-species protective <em>Leishmania</em> antigen and its responding CD4<sup>+</sup> T cells
JF Science Translational Medicine
FD American Association for the Advancement of Science
SP 310ra167
OP 310ra167
DO 10.1126/scitranslmed.aac5477
VO 7
IS 310
A1 Mou, Zhirong
A1 Li, Jintao
A1 Boussoffara, Thouraya
A1 Kishi, Hiroyuki
A1 Hamana, Hiroshi
A1 Ezzati, Peyman
A1 Hu, Chuanmin
A1 Yi, Weijing
A1 Liu, Dong
A1 Khadem, Forough
A1 Okwor, Ifeoma
A1 Jia, Ping
A1 Shitaoka, Kiyomi
A1 Wang, Shufeng
A1 Ndao, Momar
A1 Petersen, Christine
A1 Chen, Jianping
A1 Rafati, Sima
A1 Louzir, Hechmi
A1 Muraguchi, Atsushi
A1 Wilkins, John A.
A1 Uzonna, Jude E.
YR 2015
UL http://stm.sciencemag.org/content/7/310/310ra167.abstract
AB 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.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.