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Title: The role of gamma interferon in the pathogenesis of murine gammaherpesvirus-68
Author: Gangadharan, Babunilayam
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2006
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Intranasal infection of gamma interferon receptor knockout (IFNγR-/-) mice with murine gammaherpesvirus - 68 (MHV-68) causes unique pathological changes in the spleen characterised by development and resolution of fibrosis. Delineation of virological, cellular and molecular events taking place in the spleen during these pathological changes was the main objective of this study. Sequential histopathological and cellular characterisation studies showed early invasion of lymphoid follicles (harbouring latently infected B-lymphocytes) with CD4+ and CD8+ T-lymphocytes. Concomitantly, invasion of alternatively activated macrophages characterised by arginase-1 expression was observed. These events were followed by a reduction in the number of B-lymphocytes and development of a ‘fibrotic cage’ around the shrinking lymphoid follicles. In spite of the decrease in the number of B-lymphocytes, the number of latently infected cells showed a progressive increase until the development of fibrosis. During fibrosis, a dramatic reduction in the number of latently infected cells was observed followed by repopulation of lymphoid follicles with B-lymphocytes indicating a recovery phase of the fibrotic response. These observations suggest that: 1) The progressive reduction and re-population of B-lymphocytes in the lymphoid follicles of the spleen constituted the primary events during the development and resolution of fibrosis respectively. 2) Fibrosis as a host response mechanism is able to contain the expansion of latently infected cells in the spleen. 3) Presence of latently infected cells might be the trigger for fibrosis development by preventing the re-population of lymphoid follicles. The role of IFNγ responsiveness of bone marrow derived cells in the pathogenesis of splenic fibrosis was investigated by generating radiation bone marrow chimera mice and subsequent infection with MHV-68. The study showed that, replacing the bone marrow derived cells in IFNγR-/- mice with bone marrow derived cells from wild type mice prevented the development of splenic fibrosis following MHV-68 infection. Other pathological changes occurred in the lung, liver, aorta and spleen of IFNγR-/- mice infected with MI-IV-68. Focal areas of interstitial fibrosis were observed in the lung during day 12-16 post infection. At the same time, cuffing of pulmonary vessels with primarily mononuclear cells was observed. A few of the infiltrating cells were productively infected with MHV-68 which coincided with clearing of productive infection from alveolar epithelial cells. The change in the tropism of viral infection may be related to the development of fibrosis.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available