Item – Thèses Canada

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Numéro d'OCLC
1013747709
Lien(s) vers le texte intégral
Exemplaire de BAC
Auteur
Ricciardi, Alessandra,
Titre
Preclinical characterization of the protection and immune response elicited by immunizations with Schistosoma mansoni cathepsin B
Diplôme
Ph. D. -- McGill University, 2017
Éditeur
[Montreal] : McGill University Libraries, [2017]
Description
1 online resource
Notes
Thesis supervisor: Momar Ndao (Supervisor).
Includes bibliographical references.
Résumé
"Schistosomiasis is a neglected tropical disease caused by freshwater flatworms. The parasite eggs become trapped in host tissues and, as a consequence of the stimulated immune response, promote fibrosis leading to severe organ damage. Schistosomiasis is a chronic disease, and it is a major public health concern due to its significant negative impact on quality of life. Mass drug administration with praziquantel is the mainstay of schistosomiasis control. It has long been recognized that the sole use of praziquantel to control schistosomiasis has important limitations. In particular, drug treatment does not prevent re-infection; thus, requiring constant drug delivery to endemic regions which is unsustainable in the long term. Furthermore, overuse of praziquantel raises concerns of drug resistance. There is therefore a strong incentive to develop a vaccine against schistosomiasis. Even a partially effective vaccine, could significantly decrease disease morbidity and transmission. Our group has expressed the candidate vaccine antigen Schistosoma mansoni Cathepsin B (Sm-Cathepsin B). This protein is an immunogenic cysteine peptidase found in the parasite gut. The overall goal of this thesis was to characterize Sm-Cathepsin B vaccine formulations. Our first objective was to assess the protective potential of a Sm-Cathepsin B formulation containing CpG. We used a C57BL/6 mouse model of schistosomiasis. Mice immunized with our Sm-Cathepsin B formulation had significantly lower parasite burden compared to control mice (54%-59% protection levels). The Sm-Cathepsin B + CpG immunizations elicited a biased Th1 response characterized by elevated levels of IgG2c, IFNɣ, and TNF[alpha]. Next, we sought to examine the effect of a less immune-biasing adjuvant. To this end, we used the mouse model of schistosomiasis to test a Sm-Cathepsin B vaccine formulated with the squalene based adjuvant Montanide ISA 720 VG. Using this formulation, we achieved 56%-62% protection. The formulation elicited a mixed Th1/Th2 response consisting of elevated levels of IFNɣ, TNF[alpha], IL-4, IL-5, and IgG1. Both tested Sm-Cathepsin B formulations generated similar protection levels. However, they induced very different immune responses. To fully understand the vaccine-induced protection, we needed to characterize the underlying immune mechanisms. Using an in vitro parasite killing assay, we showed that the anti-parasitic effect in the Sm-Cathepsin B + Montanide immunized animals required the presence of both CD45+ cells (leukocytes) and antibodies; thus, suggesting an antibody-dependent cell-mediated mechanism. Differently, high parasite killing in the Sm-Cathepsin B + CpG group, as well as an unadjuvanted Sm-Cathepsin B group, was independent of the presence of antibodies; thus, suggesting a dominant cellular effect. A more in-depth characterization revealed the cell populations mediating the protection induced by the different vaccine formulations. The anti-parasitic effect observed with the Sm-Cathepsin B + Montanide group was dependent on the presence of CD4+ T cells and Natural Killer (NK) cells. CD4+ T cells are likely activating the NK cells which are then involved in antibody-dependent cell-mediated cytotoxicity. For the Sm-Cathepsin B + CpG group, CD8+ T cells were shown to be the main effectors mediating parasite killing. Lastly, parasite killing in the unadjuvanted Sm-Cathepsin B group was mediated by CD4+ T cells. In summary, we have demonstrated the protective efficacy of two different Sm-Cathepsin B vaccines, and we have begun to characterize the underlying immune mechanisms mediating Sm-Cathepsin B vaccine-induced protection. Overall, the results of this thesis represent significant progress in the development and understanding of a potential vaccine formulation against schistosomiasis. " --
Autre lien(s)
digitool.Library.McGill.CA
escholarship.mcgill.ca
escholarship.mcgill.ca
Sujet
Microbiology & Immunology