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The effect of cytomegalovirus infection on molecules affecting leukocyte recruitment and migration

Craigen, Jennifer L.; (1997) The effect of cytomegalovirus infection on molecules affecting leukocyte recruitment and migration. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

The recruitment of particular subsets of leukocytes to sites of inflammation and infection is thought to be governed by specific patterns of adhesion molecule expression and chemokine production. The changes in the expression of adhesion molecules, Class I HLA, and the production of chemokines following CMV infection of fibroblasts were investigated. Class I HLA was downregulated on the surface of CMV infected fibroblasts, and upregulated on uninfected bystander cells in infected cultures, the latter by a mechanism involving Interferon p. CMV infection was found to upregulate the surface expression of ICAM-1 and LFA-3 in fibroblasts. This was found to be a direct effect of viral infection, and was independent of cytokine production by infected cells. The upregulation of ICAM-1 and LFA-3 were not prevented by treatment of the cells with the antiviral agents ganciclovir and foscarnet, showing that expression of CMV late proteins was not required for the effect. In addition, the adhesion molecule upregulation was prolonged and enhanced by antiviral treatment. The functional effects of adhesion molecule upregulation on T cell adhesion were investigated. It was found that adhesion of both resting and activated T cells took place at increased levels to CMV infected fibroblasts, but that this was not due to selective adherence of a particular subset of T cells to infected cells. Adhesion of activated T cells to CMV infected fibroblasts also occurred at increased levels compared to uninfected fibroblasts, and was mediated predominantly via the ICAM-1/LFA-1 adhesion pathway. Expression of two chemokines, interleukin-8 (IL-8), an [beta] chemokine, and MCP- 1 (monocyte chemoattractant protein-1), a [beta] chemokine, were investigated. IL-8 was found to be produced at increased levels by infected fibroblasts, and infected supernatants were found to enhance neutrophil migration across endothelial monolayers. This was specifically due to increased IL-8 levels in the supernatants. Steady state levels of MCP-1 mRNA were increased following CMV infection, but this was not accompanied by an increase of MCP-1 protein in the infected supernatants. In contrast, supernatants from infected cells had lower levels of MCP-1 than those from uninfected cells. Recombinant MCP-1 was lost from solution following incubation with CMV infected cells. This was probably due to the sequestering of MCP-1 by infected cells by the CMV- encoded [beta] chemokine receptor. Migration of T cells from some donors across endothelial monolayers was increased in response to supernatants from infected fibroblasts. T cells of the memory phenotype (CD45 RO and CD45 RB|ow) migrated at increased levels in response to supernatants from either iii infected or uninfected fibroblasts, particularly those with high expression of LFA-1. There is a fine balance between a beneficial and destructive immune response. Increased adhesion and migration of leukocytes in response to changes in adhesion molecule and chemokine expression may contribute to immune mediated tissue damage, which is a characteristic of certain types of CMV disease.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: The effect of cytomegalovirus infection on molecules affecting leukocyte recruitment and migration
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Health and environmental sciences
URI: https://discovery.ucl.ac.uk/id/eprint/10100672
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