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.

METHODOLOGY:

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: Asha Jayakumar, Tiago M Castilho, Esther Park, Karen Goldsmith-Pestana, Jenefer M Blackwell, Diane McMahon-Pratt
• Journal: PLoS neglected tropical diseases (PLoS Negl Trop Dis) Vol. 5 Issue 6 Pg. e1204 (Jun 2011) ISSN: 1935-2735 [Electronic] United States
• PMID: 21695103 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Interleukin-13
• Leishmaniasis Vaccines
• Protozoan Proteins
• Tlr2 protein, mouse
• Toll-Like Receptor 1
• Toll-Like Receptor 2
• Vaccines, DNA
• Vaccines, Synthetic
• Viral Vaccines
• Interleukin-10
• Interferon-gamma
• Peroxidases
• tryparedoxin peroxidase

Topics

• Animals
• CD4-Positive T-Lymphocytes (immunology)
• CD8-Positive T-Lymphocytes (immunology)
• Disease Models, Animal
• Female
• Genetic Vectors
• Immunization, Secondary (methods)
• Interferon-gamma (metabolism)
• Interleukin-10 (metabolism)
• Interleukin-13 (metabolism)
• Leishmania (genetics, immunology)
• Leishmaniasis (immunology, prevention & control)
• Leishmaniasis Vaccines (administration & dosage, immunology)
• Mice
• Mice, Inbred BALB C
• Peroxidases (genetics, immunology)
• Protozoan Proteins (genetics, immunology)
• Rodent Diseases (immunology, prevention & control)
• Toll-Like Receptor 1 (immunology)
• Toll-Like Receptor 2 (immunology)
• Vaccination (methods)
• Vaccines, DNA (administration & dosage, immunology)
• Vaccines, Synthetic (administration & dosage, immunology)
• Vaccinia virus (genetics)
• Viral Vaccines (administration & dosage, immunology)