The life-long infection by varicelloviruses is characterized by a fine balance between the host immune response and immune evasion strategies employed by these viruses. Virus-derived peptides are... Show moreThe life-long infection by varicelloviruses is characterized by a fine balance between the host immune response and immune evasion strategies employed by these viruses. Virus-derived peptides are presented to cytotoxic T-lymphocytes by MHC I molecules. The transporter associated with antigen processing (TAP) transports the peptides from the cytosol into the endoplasmic reticulum, where the loading of MHC I molecules occurs. The UL49.5 protein of the varicelloviruse bovine herpesvirus 1 (BHV-1) is a potent inhibitor of TAP-mediated peptide transport. The viral protein prevents MHC I maturation by rendering the TAP complex in a translocation incompetent state. In addition, TAP proteins are degraded in the presence of BHV-1 UL49.5. The chapters 2 to 4 of this thesis focus on the functional dissection of BoHV-1 UL49.5 and aim to identify its target domain within the TAP complex. All herpesviruses sequenced to date code for a UL49.5 homolog. However, in chapter 5 and 6 we show that only a few viruses belonging to the genus Varicellovirus encode a TAP-inhibiting UL49.5. The applicability of the UL49.5 proteins to study and modify pathways of antigen presentation is demonstrated in chapter 7 and 8. Chapter 9 describes the identification of a TAP inhibitor in cowpox virus Show less
From the earliest times of their evolution, multi-cellular organisms have been defending themselves against infectious agents like nucleic acids, viruses, bacteria, fungi and parasites. Continuous... Show moreFrom the earliest times of their evolution, multi-cellular organisms have been defending themselves against infectious agents like nucleic acids, viruses, bacteria, fungi and parasites. Continuous selection pressure resulted in the development of sophisticated immune systems, which in their adaptive forms have exquisite specificity as well as memory for pathogen antigens. On the other hand, infectious agents developed elaborate strategies to escape from, or counteract, host defense mechanisms. Viruses are totally dependent upon host cells for replication and have developed an impressive variety of mechanisms to shield themselves from being detected by the host immune system. The subject of this thesis concerns a particular example of how viruses, specifically some members of genus Varicellovirus, counteract an important step in one of the acquired immunity pathways: the presentation of antigen by Major Histocompatibility Complex (MHC) class I molecules to cytotoxic T-cells. This thesis describes the discovery of a new family of proteins that inhibit the Transporter associated with Antigen Processing (TAP), and sets the first steps towards the explanation of how these inhibitors interfere with antigen transport by the MHC class I loading complex. Show less
