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Citation: Kedzierska K, Curtis JM, Valkenburg SA, Hatton LA, Kiu H, et al. (2012) Induction of Protective CD4+ T Cell-Mediated Immunity by a Leishmania Peptide Delivered in Recombinant Influenza Viruses. PLoS ONE 7(3): e33161. doi:10.1371/journal.pone.0033161
Katherine Kedzierska1*, Joan M. Curtis2,3, Sophie A. Valkenburg1, Lauren A. Hatton1, Hiu Kiu2,3, Peter C. Doherty1,4, Lukasz Kedzierski2,3*
1 Department of Microbiology and Immunology, The University of Melbourne, Parkville, Victoria, Australia, 2 The Walter + Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia, 3 Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia, 4 Department of Immunology, St. Jude Children?s Research Hospital, Memphis, Tennessee, United States of America
Abstract Top
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 LACK158?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 LACK158?173-specific CD4+ T cell responses protected against live L. major infection. We show that vaccination with influenza-LACK158?173 triggers LACK158?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 LACK158?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.
Katherine Kedzierska1*, Joan M. Curtis2,3, Sophie A. Valkenburg1, Lauren A. Hatton1, Hiu Kiu2,3, Peter C. Doherty1,4, Lukasz Kedzierski2,3*
1 Department of Microbiology and Immunology, The University of Melbourne, Parkville, Victoria, Australia, 2 The Walter + Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia, 3 Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia, 4 Department of Immunology, St. Jude Children?s Research Hospital, Memphis, Tennessee, United States of America
Abstract Top
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 LACK158?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 LACK158?173-specific CD4+ T cell responses protected against live L. major infection. We show that vaccination with influenza-LACK158?173 triggers LACK158?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 LACK158?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.