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Herpes Virus Manipulation of Host Cell Glycosylation

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Herpes Virus Manipulation of Host Cell Glycosylation Herpesvirus-induced expression of sLex and related O- linked glycans in the infected cell Kristina Nyström Department of Infectious Medicine 2007 Kristina Nyström Herpesvirus-induced expression of sLex and related O-linked glycans in the infected cell Department of Infectious Medicine Göteborg University, 2007 Print: Geson, Kungsbacka, Sweden ISBN: 978-91-628-7271-7 Abstract Lewis antigens constitute a family of fucosylated carbohydrate antigens (glycotopes), involved in leukocyte homing and related immunological phenomena. These glycotopes are only expressed restrictedly in normal cells, but are induced at appropriate occasions. It is well established that many tumors “hijack” Lewis glycotopes for e.g. extravasation and metastasis, and recent data indicate that also human retroviruses may use a similar strategy for colonization of distal tissues. The overall goal of the present thesis was to explore the prerequisite for this phenomenon to occur in cells infected with herpesviruses, a virus family where persistent infections and immune evasion are important hallmarks. Using confocal immunofluorescence, neo-expression of Lewis antigens was found on cells infected with herpes simplex virus type-1 (HSV-1), varicella-zoster virus (VZV), and cytomegalovirus (CMV). However, whereas the neurotropic viruses VZV and HSV-1 induced sialyl Lewis x (sLex), CMV induced Lewis y (Ley) at the surface of the infected cells. Real time RT-PCR methods for transcriptional analysis of all known human fucosyltransferase genes (FUT) were developed to determine the mechanism behind virus-specific induction of different glycotopes. The herpesviruses investigated were all able to induce transcription of FUT3, FUT5 and FUT6 relevant for sLex and Ley synthesis whereas only CMV induced FUT1, necessary for Ley expression. In most cases the transcriptional activity of these genes was several orders of magnitude larger in virus- infected cells compared to uninfected cells. The viral factors causing neo-expression of glycotopes were explored using FUT5 and the HSV-1 infected cell as a model system. It was found that the transcripts of the immediate early viral gene, designated ICP0, was able to induce FUT5 transcription without assistance of the translated gene product. This finding explained the extremely early occurrence of host FUT5 RNA, detectable as early as one hour post infection. However, several other viral factors were engaged in regulation of the FUT5 transcription downstream the ICP0 induction. The viral glycoprotein gC-1 was identified as a probable candidate as a carrier of O-linked glycans and important regulatory elements of the O-glycosylation sequon of gC-1 were characterized. These regulatory elements were decisive for the social behavior of virus-infected cells in culture. The conclusion of the present work is that herpesviruses possess powerful mechanisms for viral control of the expression of selectin ligands and similar glycotopes, of relevance for tumor metastasizing and tissue invasion of human transforming retroviruses. sLex and Ley constitute targets for development of cancer chemotherapy, but further investigation is necessary to determine whether this approach is applicable also for treatment of herpesvirus-infections. 3 List of Publications I. Mårdberg K, Nyström K, Tarp MA, Trybala E, Clausen H, Bergström T, Olofsson S. Basic amino acids as modulators of an O-linked glycosylation signal of the herpes simplex virus type 1 glycoprotein gC: functional roles in viral infectivity. Glycobiology 2004; 14(7):571-81. II. Nyström K, Biller M, Grahn A, Lindh M, Larson G, Olofsson S. Real time PCR for monitoring regulation of host gene expression in herpes simplex virus type 1-infected human diploid cells. J Virol Methods 2004; 118(2):83-94. III. Nyström K, Grahn A, Lindh M, Brytting M, Mandel U, Larson G, Olofsson S. Virus- induced transcriptional activation of host FUTgenes associated with neo-expression of Ley in cytomegalovirus- and sialyl-Lex in varicella-zoster virus-infected diploid human cells. Glycobiology 2007; 17(4): 355-366. IV. Nyström K, Elias P, Larson G, Olofsson S. Herpes simplex virus type 1 ICP0-activated transcription of host fucosyltransferase genes resulting in neo-expression of sialyl-Lex in virus-infected cells. In Manuscript. 4 Table of Contents Abstract ..................................................................................................................... 3 List of Publications .................................................................................................. 4 Table of Contents ..................................................................................................... 5 List of Abbreviations and Acronyms ...................................................................... 6 Introduction ............................................................................................................... 7 Aims of the present thesis ....................................................................................... 8 Herpesviridae .......................................................................................................... 9 Viral Replication .....................................................................................................10 Transcription of viral and cellular genes in the HSV-1-infected cell ........................11 Glycoprotein C and glycosylation of viral glycoproteins ..........................................11 Glycosylation topology of gC-1 ...............................................................................13 Lewis and related antigens .....................................................................................13 Lewis antigens as selectin ligands ......................................................................14 Lewis antigens in cancer .....................................................................................15 Lewis antigens as viral receptors ........................................................................15 Fucosyltransferases ...............................................................................................15 Methodological considerations ..............................................................................17 Cell culture, herpesvirus strains, and procedures for viral infection .......................17 In vitro glycosylation of gC-1 mutant ......................................................................17 Transcriptional analysis ..........................................................................................17 Lewis antigen expression .......................................................................................18 Results......................................................................................................................19 O-glycosylation signal features (I) ..........................................................................19 Establishment of Real time RT-PCR for transcriptional analysis (II).......................22 Lewis antigen expression in herpes virus infected cells (II, III and IV)....................22 Viral factors responsible for FUT5 induction .......................................................23 General Discussion .................................................................................................27 Acknowledgements .................................................................................................34 References ...............................................................................................................35 5 List of Abbreviations and Acronyms CHX Cycloheximide CMV Cytomegalovirus CS Chondroitin sulfate DC Dendritic cell DC-SIGN Dendritic cell-specific ICAM-3-grabbing nonintegrin dl1403 HSV-1 mutant with deletion in ICP0 E Early FITC Fluorescein Iso-thiocyanate Fuc fucose Fuc-TI fucosyltransferase 1 FUT Fucosyltransferase gene Gal galactose GalNAc N-acetyl galactosamine gC, gD glycoprotein C, D GlcNAc N-acetylglucosamine Glycotope Acronym for carbohydrate epitopes, defined by a specific antibody or lectin GMK Green monkey kidney cells HEL Human embryonic lung fibroblasts HS Heparan sulfate HSV-1 Herpes simplex virus type-1 HSV114,117 HSV-1 mutated at gC aminoacid 114 and 117 HTLV-1 Human T-cell leukemia virus type-1 ICP0 Infected cell protein 0 IE immediate early L Late LAT Latency associated transcript Lea Lewis a Leb Lewis b Lex Lewis x Ley Lewis y MOI Multiplicity of infection ND10 Nuclear domain 10 PCR Polymerase chain reaction pgC Precursor gC sLea sialyl Lewis a sLex sialyl Lewis x TRITC Tetramethyl Rhodamine Iso-Thiocyanate tsS HSV-1 temperature sensitive mutant in ori binding protein tsK HSV-1 temperature sensitive mutant in ICP4 VHS Virion host shut-off VZV Varicella-zoster virus 6 Introduction Lewis antigens, carbohydrates closely related to the ABO histo-blood group antigens, are important ligands for selectins, whose interactions are of relevance for leukocyte homing. Selectin binding of leukocytes via sialyl Lewis x (sLex) and related antigens allow cells to bind weakly to the epithelial cells, forcing the leukocytes to roll along the blood vessel, resulting in tighter bindings and eventually passing of the leukocyte across the epithelial barrier. The powerful leukocyte homing mechanism, offered by selectin interactions with their ligands, has been hijacked by different types of tumors during metastasis. This allows the circulating tumor cells to pass through the blood vessel wall. In addition to sLex, a related carbohydrate structure,
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