The human body defends itself from pathogen infections through very complicated processes. They include host innate, adaptive and cellular intrinsic immunities. Host innate and adaptive immunities have been studied extensively in past decades, and more detail is being continuously revealed to us. Cellular intrinsic immunity has been recognised in more recent decades and has attracted great interest among researchers. Many cellular proteins have been identified to repress viral infections such as HIV, Influenza and Herpes Viruses. One aspect of intrinsic immunity, or intrinsic resistance, to herpes virus infections was demonstrated to involve nuclear structures known as ND10 (nuclear domain 10). With accumulating evidence about ND10, many components of ND10 that are involved in intrinsic immunity were identified. In the early stage of infection, HSV-1 and HCMV genomes become associated with ND10 components, which include PML, Sp100 and the hDaxx-ATRX complex. All these proteins were identified to repress HSV-1 and HCMV infection and replication. Viral proteins that have been identified to interact with PML, Sp100 and the hDaxx-ATRX complex and that counteract their anti-viral activities include ICP0 from HSV-1 and IE1 and pp71 from HCMV. Furthermore, recently studies on EBV proteins identified BNRF1 to interact with the hDaxx-ATRX complex, while EBNA1 appears to down regulate PML and EBNA-LP is involved in Sp100 dispersion from ND10. The evidence above raises the possibility that ND10 interacting proteins from different herpes viruses may be functionally interchangeable. IE1 interacts with ND10 to de-sumoylate and disperse PML and Sp100. There is also evidence of interaction between IE1 and hDaxx complex. pp71 was demonstrated to interact with and promote the degradation of hDaxx, and to disrupt the hDaxx-ATRX complex to stimulate HCMV infection and replication. For HSV-1, ICP0 was identified to degrade PML and Sp100, and counteract the effects of the hDaxx-ATRX complex on viral infection repression. Therefore, IE1 and pp71 were analysed for their ability to complement ICP0 null HSV-1, and they were demonstrated to stimulate ICP0 null HSV-1 infection to a large extent. In this study, the reverse investigation was analysed. To extend the study, EBV proteins that interact with ND10 were also analysed in stimulating HSV-1 and HCMV mutant viruses. The major findings in this thesis are summarised as follows: 1. IE1 and pp71 can separately and cooperatively stimulate ICP0 null HSV-1 infection in HepaRG cells and human fibroblasts. 2. The expression of IE1 and ICP0 in human fibroblasts can increase wt HCMV infection. 3. ICP0 can complement pp71 null HCMV infection but not IE1 null HCMV. 4. Two sequences that are essential for IE1 functions were identified and one IE1 sequence was identified to be HCMV specific on promoting viral infection and replication. 5. EBV proteins that interact with ND10 can stimulate ICP0 null HSV-1 and pp71 null HCMV infection. The data in this thesis demonstrated that the combination of IE1 and pp71 is interchangeable with ICP0 in HSV-1 infection and EBV proteins that interact with ND10 partially complement ICP0 null HSV-1 infection. The results indicated that the integrity of ND10 is an important part of cellular intrinsic resistance to HSV-1 infection. The observation on ICP0 complementing IE1 deletion HCMV indicated the HCMV specific role of IE1. ICP0, BNRF1 and pp71 are all involved in counteracting the hDaxx-ATRX complex repression on viral infection and replication. These three proteins were demonstrated to complement ICP0 null HSV-1 and pp71 null HCMV infection, which indicates the importance of the hDaxx-ATRX complex on repressing herpes viruses infection. Even though solid data in this thesis has confirmed the ND10 repression on herpes virus infection and the herpes viruses from different subfamilies counteracting this repression through different viral proteins, more detail about this intrinsic resistance mechanisms still require extensive investigation.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:659404 |
| Date | January 2015 |
| Creators | Lu, Yongxu |
| Publisher | University of Glasgow |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://theses.gla.ac.uk/6594/ |
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