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Permanent link (DOI): https://doi.org/10.7939/R30863D6D

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Regulation of Natural Killer Cell Ligands by Poxvirus Infection Open Access

Descriptions

Other title
Subject/Keyword
Natural Killer Cells
Vaccinia Virus
NKR-P1A
NKR-P1B
CLEC2D
Clr-b
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Williams, Kinola J N
Supervisor and department
Burshtyn, Deborah (Medical Microbiology and Immunology)
Examining committee member and department
Hitt, Mary (Oncology)
Grant, Michael (BioMedical Sciences)
Marchant, David (Medical Microbiology and Immunology)
Agrawal, Babita (Surgery)
Department
Department of Medical Microbiology and Immunology
Specialization
Immunology
Date accepted
2015-09-04T14:25:18Z
Graduation date
2015-11
Degree
Doctor of Philosophy
Degree level
Doctoral
Abstract
Natural Killer (NK) cells are a major part of the innate immune defence against viral infection and tumours. However, our understanding of how NK cells can be exploited for antiviral and antitumor therapy is still in its infancy. We are interested in the interplay between NK cells and Vaccinia Virus (VACV) since VACV is a basis of vaccine design and has the potential as an oncolytic virus for tumor therapy. Currently, we are focused on how VACV affects the ligands of NK receptors belonging to the NKR-P1 family. This family of C-type lectin-related receptors contains members that can stimulate or inhibit NK cell function. We first studied the impact of VACV and Ectromelia virus (ECTV) infection on expression of the mouse CLEC2D protein, Clr-b, and Clr-b mediated protection from mouse NK cells. We observed a loss of Clr-b cell surface protein upon infection of murine cell lines and bone marrow derived macrophages with VACV and ECTV. The reduction of Clr-b is more rapid than MHC class I, the prototypic ligand of NK cell inhibitory receptors. Reduction of Clr-b requires an active viral infection but not expression of late viral genes. The loss of Clr-b mRNA appears to be delayed behind loss of Clr-b surface protein. Finally, Clr-b mediated protection from NK cells is lost following VACV infection. Subsequently, we studied the influence of VACV infection of the expression of human CLEC2D and CLEC2D mediated protection from human NK cells. Human CLEC2D is constitutively expressed on transformed cells and it is believed that cells may need to be stimulated to induce expression. We observed a rapid increase in CLEC2D cell surface protein as detected by 4C7 antibody staining upon VACV infection of human cell lines that gradually decreased over time. The increase of 4C7 staining requires an active infection with the presence of an early viral protein, however, a late viral protein enhances the increase in the 4C7 reactive protein. We discovered that all cells may express an isoform of the 4C7 reactive protein, and that they all contain an intracellular pool of the 4C7 reactive protein. Although VACV infection causes the upregulation the 4C7 reactive protein, it does not increase surface expression of isoform 1 of CLEC2D which is reported to bind to NKR-P1A (85). Given the lack of increase in isoform 1, NK cells did not recognize infected cells through NKR-P1A. My results suggest that Clr-b is another mechanism of the missing self recognition system that may act earlier than MHC I recognition in rodents. In contrast, in humans, the function of CLEC2D is still undergoing investigation and my results suggest that intracellular pools of a 4C7 reactive protein may be manipulated by VACV infection. However the function of the CLEC2D isoforms involved in the infection remains an open question. Collectively, these data augment our knowledge in viral evasion and host response to infection. Further studies of this process could facilitate improved vaccine design and cancer therapy that currently uses VACV as a platform.
Language
English
DOI
doi:10.7939/R30863D6D
Rights
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
Citation for previous publication
Kinola J N Williams, Evan Wilson, Chelsea L Davidson, Oscar A Aguilar, Li Fu, James R Carlyle and Deborah N Burshtyn. 2012. Poxvirus Infection Associated Down Regulation of C-Type Lectin-Related-b Prevents NK Cell Inhibition by NK Receptor Protein 1B. J Immunol; 188: 4980-91.

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