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1. Wang, Xuan. Function of M4 protein in vitro and in vivo.

Degree: PhD, 2013, University of Edinburgh

Herpesviruses are ubiquitous in both humans and animals and can cause life-threatening disease. The discovery of murine gammaherpesvirus 68 (MHV-68), which has many similarities in genome and pathogenesis as the human pathogens Epstein-Barr virus and Kaposi’s sarcoma-associated herpesvirus, provides a model for further investigation of the pathogenesis of gammaherpesviruses. The M4 gene was found to be at the left end region of MHV-68 genome. The presence of the M4 protein is required during the early establishment of MHV-68 latency. However, the function of M4 protein remains unclear. The aim of this project was to investigate the function of the M4 protein in vitro and during infection. By using an ELISA, the recombinant M4 protein was shown to bind several Cxc-chemokines and stop the interaction between Cxcl4 and GAGs. The role of M4 protein during MHV-68 lytic infection and in the early establishment of latency was studied by comparing the pathogenesis of virus which does not express M4 (M4stop) and wild type virus (WT). Compared to WT infection, this study found that M4stop was decreased in the lungs at day 8 post infection (p.i.). At the same time point, the viral loads were higher in M4stop infected spleens, which was accompanied by increased expression of the CD4+ T cell activation marker PD-1 and the macrophage activation marker CD69. However, at day 14 p.i., the M4stop infected spleens had lower viral loads, and the expression of CD69 was decreased on CD4+, CD8+ T cells, B cells and macrophages. Furthermore, gene expression PCR arrays were used to investigate how cellular activation and inflammation were transcriptionally regulated. It has been found that the transcription of several genes, which are involved in germinal centre development, was lower in the spleens of WT infected mice at day 12 and 14 p.i. compared to day 10 p.i. of WT infection, as well as day 12 and 14 p.i. of M4stop infection. In addition, the percentage of germinal centre B cells was found to be higher in spleens infected with M4stop at day 10 p.i.. However, there was no difference in percentages of TFH and plasma cells in the spleens. Finally, in order to understand the role of IFN-γ in control of infection in M4stop infected mice, IFN-γR-/- mice were infected with M4stop and WT. Although there were differences in pathogenesis between WT and M4Stop virus infected IFN-γR-/- mice, there was no clear evidence that M4 function is involved in inhibiting IFN-γ pathways. In this study, we found M4 can disturb the interaction of chemokine and GAGs and might delay virus trafficking to the spleen, which could lead to a reduction of cellular activation. M4 may also impair the development of germinal centres at the beginning of latent infection in the spleens.

Subjects/Keywords: 572; MHV-68; M4 protein; Chemokine binding protein; germinal centre; GC

…181 Role of M4 in MHV-68 pathogenesis in IFN-R-/- Mice… …of the genome of MHV-68 and its mutants ....................... 30 Figure 1.2 A… …170 Figure 5.3 The gating strategy of GC B cells after MHV-68 infection… …associated transcript LB LGs LMP LP M4sotp MACS MCD MHV-68 mK3 MLN MOI MV NBF Luria-Bertani late… …multicentric Castleman disease murine gammaherpesvirus 68 MHV-68 K3 mediastinal lymph node… 

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APA (6th Edition):

Wang, X. (2013). Function of M4 protein in vitro and in vivo. (Doctoral Dissertation). University of Edinburgh. Retrieved from http://hdl.handle.net/1842/8195

Chicago Manual of Style (16th Edition):

Wang, Xuan. “Function of M4 protein in vitro and in vivo.” 2013. Doctoral Dissertation, University of Edinburgh. Accessed September 23, 2019. http://hdl.handle.net/1842/8195.

MLA Handbook (7th Edition):

Wang, Xuan. “Function of M4 protein in vitro and in vivo.” 2013. Web. 23 Sep 2019.

Vancouver:

Wang X. Function of M4 protein in vitro and in vivo. [Internet] [Doctoral dissertation]. University of Edinburgh; 2013. [cited 2019 Sep 23]. Available from: http://hdl.handle.net/1842/8195.

Council of Science Editors:

Wang X. Function of M4 protein in vitro and in vivo. [Doctoral Dissertation]. University of Edinburgh; 2013. Available from: http://hdl.handle.net/1842/8195

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