Investigation of the molecular alterations of macrophage function during intracellular infection by Leishmania donovani revealed both adverse and positive influences of this protozoan on host cell function. Chapter I delineates a negative effect which this parasite has on signal transduction pathways in its host cell. In macrophages put in contact, or infected with L. donovani, c-fos gene expression mediated through protein kinase A was unaffected under conditions where there was an impairment of protein kinase C-mediated c-fos gene expression. Selective impairment of protein kinase C-, or, calmodulin-dependent protein kinase-mediated signal transduction in the macrophage was found to influence the establishment of infection. Chapters two and three describe a positive enhancement of macrophage function by L. donovani. Intramacrophage infection with L. donovani was shown to enhance host cell viability in the absence of growth factor. This was attributable to the elaboration of a soluble factor(s) by infected macrophages into the cell culture supernatant, which enhanced macrophage viability in a manner independent of cell replication. Further characterization of the mechanism of this enhancement revealed that L. donovani infection, and lipophosphoglycan, inhibited macrophage death by apoptosis. Cell supernatants derived from L. donovani infected cells were also capable of inhibiting macrophage apoptosis. To identify the active factor in infected cell supernatants, the cytokine gene expression profile of L. donovani infected macrophages was delineated and possible candidate cytokines were further investigated. Levels of TNF-$ alpha$ capable of causing an abrogation of apoptosis were found to be produced by infected macrophages. However, antibody neutralization of TNF in infected cell cultures could not reverse the inhibition of apoptosis by L. donovani, implicating the involvement of multiple factors in the abrogation of apoptosis by L. donovani.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.41724 |
| Date | January 1994 |
| Creators | Moore, Kathryn J. |
| Contributors | Matlashewski, Greg (advisor) |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Institute of Parasitology.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 001396017, proquestno: NN94689, Theses scanned by UMI/ProQuest. |
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