title: TLR1/2 activation during heterologous prime-boost vaccination (DNA-MVA) enhances CD8+ T Cell responses providing protection against Leishmania (Viannia).
abstract: BACKGROUND
  Leishmania (Viannia) parasites present particular challenges, as human and murine immune responses to infection are distinct from other Leishmania species, indicating a unique interaction with the host. Further, vaccination studies utilizing small animal models indicate that modalities and antigens that prevent infection by other Leishmania species are generally not protective.
  
  
  METHODS
  Using a newly developed mouse model of chronic L. (Viannia) panamensis infection and the heterologous DNA prime - modified vaccinia virus Ankara (MVA) boost vaccination modality, we examined whether the conserved vaccine candidate antigen tryparedoxin peroxidase (TRYP) could provide protection against infection/disease.
  
  
  RESULTS
  Heterologous prime - boost (DNA/MVA) vaccination utilizing TRYP antigen can provide protection against disease caused by L. (V.) panamensis. However, protection is dependent on modulating the innate immune response using the TLR1/2 agonist Pam3CSK4 during DNA priming. Prime-boost vaccination using DNA alone fails to protect. Prior to infection protectively vaccinated mice exhibit augmented CD4 and CD8 IFNγ and memory responses as well as decreased IL-10 and IL-13 responses. IL-13 and IL-10 have been shown to be independently critical for disease in this model. CD8 T cells have an essential role in mediating host defense, as CD8 depletion reversed protection in the vaccinated mice; vaccinated mice depleted of CD4 T cells remained protected. Hence, vaccine-induced protection is dependent upon TLR1/2 activation instructing the generation of antigen specific CD8 cells and restricting IL-13 and IL-10 responses.
  
  
  CONCLUSIONS
  Given the general effectiveness of prime-boost vaccination, the recalcitrance of Leishmania (Viannia) to vaccine approaches effective against other species of Leishmania is again evident. However, prime-boost vaccination modality can with modulation induce protective responses, indicating that the delivery system is critical. Moreover, these results suggest that CD8 T cells should be targeted for the development of a vaccine against infection caused by Leishmania (Viannia) parasites. Further, TLR1/2 modulation may be useful in vaccines where CD8 T cell responses are critical.
authors.affiliation: Yale University School of Public Health, New Haven, Connecticut, United States of America.
authors.forename: Asha
authors.initials: A
authors.lastname: Jayakumar
authors.forename: Tiago M
authors.initials: TM
authors.lastname: Castilho
authors.forename: Esther
authors.initials: E
authors.lastname: Park
authors.forename: Karen
authors.initials: K
authors.lastname: Goldsmith-Pestana
authors.forename: Jenefer M
authors.initials: JM
authors.lastname: Blackwell
authors.forename: Diane
authors.initials: D
authors.lastname: McMahon-Pratt
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D005822:Genetic Vectors; D007117:Immunization, Secondary / Q000379:methods; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D018793:Interleukin-13 / Q000378:metabolism; D007891:Leishmania / Q000235:genetics / Q000276:immunology*; D007896:Leishmaniasis / Q000276:immunology / Q000517:prevention & control; D054332:Leishmaniasis Vaccines / Q000008:administration & dosage / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D010544:Peroxidases / Q000235:genetics / Q000276:immunology; D015800:Protozoan Proteins / Q000235:genetics / Q000276:immunology; D012376:Rodent Diseases / Q000276:immunology / Q000517:prevention & control; D051194:Toll-Like Receptor 1 / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000276:immunology*; D014611:Vaccination / Q000379:methods; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000276:immunology*; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000276:immunology; D014616:Vaccinia virus / Q000235:genetics; D014765:Viral Vaccines / Q000008:administration & dosage / Q000276:immunology*
chemical_list: D018793:Interleukin-13; D054332:Leishmaniasis Vaccines; D015800:Protozoan Proteins; C493486:Tlr2 protein, mouse; D051194:Toll-Like Receptor 1; D051195:Toll-Like Receptor 2; D019444:Vaccines, DNA; D014614:Vaccines, Synthetic; D014765:Viral Vaccines; D016753:Interleukin-10; D007371:Interferon-gamma; D010544:Peroxidases; C110959:tryparedoxin peroxidase