Induction of Protective CD4(+) T Cell-Mediated Immunity by a Leishmania Peptide Delivered in Recombinant Influenza Viruses
AuthorKedzierska, K; Curtis, JM; Valkenburg, SA; Hatton, LA; Kiu, H; Doherty, PC; Kedzierski, L
Source TitlePLoS One
PublisherPUBLIC LIBRARY SCIENCE
University of Melbourne Author/sKedzierska, Katherine; VALKENBURG, SOPHIE; HATTON, LAUREN; Doherty, Peter; Kedzierski, Lukasz; CURTIS, JOAN; KIU, HIU
AffiliationMicrobiology and Immunology
Veterinary and Agricultural Sciences
Medical Biology (W.E.H.I.)
Document TypeJournal Article
CitationsKedzierska, K., Curtis, J. M., Valkenburg, S. A., Hatton, L. A., Kiu, H., Doherty, P. C. & Kedzierski, L. (2012). Induction of Protective CD4(+) T Cell-Mediated Immunity by a Leishmania Peptide Delivered in Recombinant Influenza Viruses. PLOS ONE, 7 (3), https://doi.org/10.1371/journal.pone.0033161.
Access StatusOpen Access
The available evidence suggests that protective immunity to Leishmania is achieved by priming the CD4(+) Th1 response. Therefore, we utilised a reverse genetics strategy to generate influenza A viruses to deliver an immunogenic Leishmania peptide. The single, immunodominant Leishmania-specific LACK(158-173) CD4(+) peptide was engineered into the neuraminidase stalk of H1N1 and H3N2 influenza A viruses. These recombinant viruses were used to vaccinate susceptible BALB/c mice to determine whether the resultant LACK(158-173)-specific CD4(+) T cell responses protected against live L. major infection. We show that vaccination with influenza-LACK(158-173) triggers LACK(158-173)-specific Th1-biased CD4(+) T cell responses within an appropriate cytokine milieu (IFN-γ, IL-12), essential for the magnitude and quality of the Th1 response. A single intraperitoneal exposure (non-replicative route of immunisation) to recombinant influenza delivers immunogenic peptides, leading to a marked reduction (2-4 log) in parasite burden, albeit without reduction in lesion size. This correlated with increased numbers of IFN-γ-producing CD4(+) T cells in vaccinated mice compared to controls. Importantly, the subsequent prime-boost approach with a serologically distinct strain of influenza (H1N1->H3N2) expressing LACK(158-173) led to a marked reduction in both lesion size and parasite burdens in vaccination trials. This protection correlated with high levels of IFN-γ producing cells in the spleen, which were maintained for 6 weeks post-challenge indicating the longevity of this protective effector response. Thus, these experiments show that Leishmania-derived peptides delivered in the context of recombinant influenza viruses are immunogenic in vivo, and warrant investigation of similar vaccine strategies to generate parasite-specific immunity.
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