Human Cytomegalovirus (huCMV) is a beta herpes virus which infects one half of the adult population and is a major cause of birth defects. CMV is also an important opportunistic pathogen which has clinical implications for immunocompromised individuals and transplant recipients. Epstein-Barr Virus (EBV) is a ubiquitous herpes virus that is usually acquired as an asymptomatic infection in all human communities. Whilst most of what is known about EBV biology relates to interaction with cells of the B lymphoid lineage, the virus can also infect epithelial cells.
This interaction can result in malignant transformation since the virus is consistently associated with nasopharyngeal carcinoma (NPC) and with a proportion of gastric adenocarcinomas. The persistence and universal prevalence of huCMV and EBV indicates that both of these viruses have developed an evolutionary survival advantage. It is known that huCMV and EBV employ a number of mechanisms to switch off protective immune responses in infected hosts. This has important implications for most standard immune based vaccine strategies which seek to elicit cell mediated immune responses in vivo. As these viruses have powerful mechanism to avoid such responses, a successful immunological targeting strategy must include ways of avoiding viral evasion mechanisms. The goal of my laboratory is to bypass huCMV and EBV mediated immune evasion by delivering single or groups of viral antigens to Dendritic cells (DC) in a way which favors their meaningful presentation on MHC class I. This involves improving our understanding of the basic cell biology of DC and identifying the best vehicles for viral antigen delivery. We are particularly interested in heat shock proteins (Hsp’s). Hsp’s are pro-inflammatory and remarkable for their ability to both activate the innate immune system and to exert specificity, which is derived from peptide binding. We find that as little as 200pM peptide bound to Mycobacterial HSP70 is sufficient to prime DC to generate cytotoxic T cells. We are currently exploring the receptors used by HSP70 to gain entry to the cell, the compartment where MHC class I is loaded and comparing the efficacy of HSP from different species.
Project: From ER Stress to Inflammation and Back
Paul A MacAry*, R. Andres Floto* , Jessica M. Boname, Tan Suet Mien, Beate Kampmann, James R Hair, Oh Seen Huey, Edith N.G. Houben, Jean Pieters, Cheryl Day, Wulf Oehlmann, Mahavir Singh, Kenneth G. C. Smith and Paul J. Lehner. Dendritic Cell Stimulation by Mycobacterial HSP70 is Mediated Through CCR5. Science 2006; 314: 454-8. (*=equal first authors).
Floto RA, Clatworthy MR, Heilbronn KR, Rosner DR, MacAry PA, Rankin A, Lehner PJ, Ouwehand WH, Allen JM, Watkins NA, Smith KG.Loss of function of a lupus-associated FcgammaRIIb polymorphism through exclusion from lipid rafts. Nature Medicine. 2005; 11: 1056-8.
Reeves MB, MacAry PA, Lehner PJ, Sissons JG, Sinclair JH. Latency, chromatin remodeling, and reactivation of human cytomegalovirus in the dendritic cells of healthy carriers. Proc Natl Acad Sci U S A. 2005; 102:4140-5.
MacAry PA*, Javid B*, Floto AR, Smith KGC, Oehlmann W, Singh M, Lehner PJ. HSP70 peptide binding mutants separate antigen delivery from dendritic cell stimulation. Immunity 2004; 95-106(* equal first authors).
MacAry PA, Lindsay M, Scott MA, Craig JI, Luzio JP, Lehner PJ. Mobilization of MHC class I molecules from late endosomes to the cell surface following activation of CD34-derived human Langerhans cells. Proc Natl Acad Sci USA. 2001; 98: 3982-7.
Wang Y, Kelly CG, Karttunen JT, Whittall T, Lehner PJ, Duncan L, MacAry PA, Younson JS, Singh M, Oehlmann W, Cheng G, Bergmeier L, Lehner T. CD40 is a cellular receptor mediating mycobacterial heat shock protein 70 stimulation of cc-chemokines. Immunity. 2001; 15: 971-83.
Teo En Wei
Lan Wan Wen
Fatimah Bte Mustafa
Snr Lab Executive
Too Chien Tei
Snr Lab Executive
Low Wei Jian
Tanusya Murali Murali