Host and Parasite Factors that Regulate Anti-Leishmania Immunity in Mice
| dc.contributor.author | Liu, Dong | |
| dc.contributor.examiningcommittee | Kung, Sam(Immunology) Yang, Xi(Medical Microbiology) Yao, Xiaojian(Medical Microbiology) | en |
| dc.contributor.supervisor | Uzonna, Jude (Immunology) | en |
| dc.date.accessioned | 2011-05-06T20:04:48Z | |
| dc.date.available | 2011-05-06T20:04:48Z | |
| dc.date.issued | 2011-05-06T20:04:48Z | |
| dc.degree.discipline | Immunology | en_US |
| dc.degree.level | Doctor of Philosophy (Ph.D.) | en_US |
| dc.description.abstract | The outcome of leishmaniasis has been shown to be both host genotype and parasite strain dependent. Understanding the role of host and parasite molecules in disease outcome will provide important information for the development of new drugs, new therapies and new vaccines against this disease. In this study, we investigated the role of a host molecule, Phosphatidylinositol 3-kinases (PI3Ks) and a parasite molecule, phosphoglycans in primary and secondary immune response against Leishmania major. We hypothesized that these host and pathogen factors coordinately influence the quality and magnitude of primary and secondary (memory) immune responses (and immunity) against Leishmania major. In the first part of my study, my results show that in the absence of phosphoglycan, antigen-presenting cells (APCs) are able to present parasite antigens to T cells more efficiently and promote a Th1 type of immune responses. However, as phosphoglycan containing molecules are important for parasite survival and virulence, the initial T cell clonal burst is impaired in lpg2-infected mice. This in turn leads to significantly impaired antigen-specific recall responses (measured by proliferation, IFN-g production and delayed-type hypersensitivity response) both in vitro and in vivo. Interestingly, despite this impairment, lpg2- L. major-infected mice were protected against secondary virulent L. major challenge similar to those that healed from WT L. major infections. In the second part of my study, I demonstrate that PI3K deficient mice are highly resistant to primary L. major infection despite impaired T cells response (proliferation and effector cytokines production). Interestingly, this enhanced resistance was not due to enhanced innate immunity or humoral immunity, but was related to reduced regulatory T cell expansion and differentiation. Surprisingly, results from healed PI3Ks deficient mice suggest that an excellent primary resistance to L. major infection does not automatically translate to secondary protective responses because healed p110 KI mice failed to efficiently control secondary L. major challenge infection. We showed that the impaired memory response was due to defective proliferation of Leishmania-specific memory T cells and the inability of central memory T cells to convert to effector memory T cells, which negatively impact on the ability of memory T cells to exit peripheral lymphoid organs and home to the cutaneous site of infection to mediate effector functions. These findings have significant impacts on our knowledge in understanding of host/pathogen interaction and will shed light on future developments of vaccine, vaccination strategy and new drugs. | en |
| dc.description.note | May 2011 | en |
| dc.format.extent | 2756749 bytes | |
| dc.format.mimetype | application/pdf | |
| dc.identifier.citation | Liu D, Uzonna JE. The p110delta isoform of phosphoinositide 3 kinase controls the quality of secondary anti-Leishmania immunity by regulating expansion and effector function of memory T cell subsets. J Immunol. 2010 Mar 15;184(6):3098-105. | en |
| dc.identifier.citation | Liu D, Zhang T, Marshall AJ, Okkenhaug K, Vanhaesebroeck B, Uzonna JE. The p110delta isoform of phosphatidylinositol 3-kinase controls susceptibility to Leishmania major by regulating expansion and tissue homing of regulatory T cells. J Immunol. 2009 Aug 1;183(3):1921-33. | en |
| dc.identifier.citation | Liu D, Kebaier C, Pakpour N, Capul AA, Beverley SM, Scott P, Uzonna JE. Leishmania major phosphoglycans influence the host early immune response by modulating dendritic cell functions. Infect Immun. 2009 Aug;77(8):3272-83. | en |
| dc.identifier.uri | http://hdl.handle.net/1993/4598 | |
| dc.language.iso | eng | en_US |
| dc.rights | open access | en_US |
| dc.subject | Immunology | en |
| dc.subject | Parasitology | en |
| dc.title | Host and Parasite Factors that Regulate Anti-Leishmania Immunity in Mice | en |
| dc.type | doctoral thesis | en_US |