Host and parasite factors that regulate secondary immunity to experimental cutaneous leishmaniasis

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dc.contributor.authorOkwor, Ifeoma
dc.contributor.examiningcommitteeFowke, Keith ( Medical Microbiology) Yang, Xi (Medical Microbiology) Ellison, Cindy (Pathology) Papadopoulou, Barbara (Laval University)en_US
dc.contributor.supervisorUzonna, Jude ( Medical Microbiology)en_US
dc.date.accessioned2015-09-08T20:12:14Z
dc.date.available2015-09-08T20:12:14Z
dc.date.issued2014-11-20en_US
dc.date.issued2015-05-29en_US
dc.date.issued2009-09en_US
dc.date.issued2013-05en_US
dc.date.issued2012-05en_US
dc.degree.disciplineMedical Microbiologyen_US
dc.degree.levelDoctor of Philosophy (Ph.D.)en_US
dc.description.abstractLeishmaniasis is a spectrum of diseases caused by several species of protozoan parasites belonging to the genus, Leishmania. The disease, which is transmitted by Sandflies, ranges from self-healing cutaneous lesions to the life-threatening visceral leishmaniasis. Cutaneous leishmaniasis, caused by L. major, is the most common form of the disease. With no vaccine available for use in humans, cutaneous leishmaniasis remains a global public health problem. Since understanding the factors that regulate effective immunity to cutaneous leishmaniasis is critical for the development of an affective vaccine and treatment strategies, the overall aim of my thesis was to decipher the host and pathogen factors that regulate immunity in cutaneous leishmaniasis. Firstly, I show that parasite dose affects the expansion of different T cell subsets following L. major infection; with low dose infection inducing more CD8+ T cells while high dose infection induced more CD4+ T cells. However, although CD8+ T cells were important for optimal primary immunity following low dose infection, they where dispensable during secondary immunity. Secondly, I found that blockade of LIGHT, (lymphotoxin like, exhibits inducible expression and competes with HSV glycoprotein D for HVEM, a receptor expressed by T lymphocytes) significantly impaired DC maturation, expression of co-stimulatory molecules, and early cytokine production (IL-12 and IFN-γ) following L. major infection. Interestingly, LIGHT was completely dispensable during secondary immunity in wild type mice but was critical for effective secondary immunity in CD40 deficient mice. Thirdly,I compared disease progression and immune response in CD40 and CD40L deficient mice infected with L. major under identical experimental conditions. I found significant differences in disease progression and immune response between CD40KO and CD40L KO mice infected with virulent L. major and treated with recombinant IL-12. My data revealed a novel pathway (CD40L-Mac-1 interaction) for IL-12 production and resistance to Leishmania major. Collectively, this thesis provides novel insights into the mechanisms involved in the development and maintenance of protective immunity against cutaneous leishmaniasis, which could lead to the development of a more efficient and effective immunotherapeutic and/or vaccination strategies against the disease.en_US
dc.description.noteOctober 2015en_US
dc.identifier.citationJournal of Immunologyen_US
dc.identifier.citationNumbereden_US
dc.identifier.citationPLoSen_US
dc.identifier.citationFrontiers Scienceen_US
dc.identifier.urihttp://hdl.handle.net/1993/30731
dc.language.isoengen_US
dc.publisherFrontiers publishersen_US
dc.publisherAmerican Association of Immunologists Incen_US
dc.publisherSpringeren_US
dc.publisherPublic Library of Scienceen_US
dc.rightsopen accessen_US
dc.subjectLeishmaniasisen_US
dc.subjectCytokineen_US
dc.subjectInterferon gammaen_US
dc.subjectT cellsen_US
dc.subjectMacrophagesen_US
dc.titleHost and parasite factors that regulate secondary immunity to experimental cutaneous leishmaniasisen_US
dc.typedoctoral thesisen_US
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