BA Hons (Cambridge, UK) Virology/Immunology; PhD (Cambridge, UK) Virology
Position: 
Acting Director, Clinical Medical Virology Centre (UQ) / Sir Albert Sakzewski Virus Research Centre (RCH)
Phone: 
+61 7 363 68138
Biography: 

I was a Postdoctoral Research Associate at Cambridge University (UK) and a Senior Research Officer at the University of Western Australia. I was appointed as Head of Virology / Infectious Diseases at the Animal Health Trust, Newmarket (UK) in 1998 and joined The University of Queensland to establish a new research unit at CMVC / SASVRC in 2006.

Research Focus and Collaborations: 

The primary research theme of my laboratory is to understand the role of herpesvirus immuno-modulatory proteins during pathogenesis. Our research is focussed on G protein-coupled receptor homologues (GPCR) encoded by the betaherpesviruses, such as human and mouse cytomegalovirus (H/ MCMV). Two gene families (‘beta-78’ and ‘beta-33’) are conserved in all betaherpesviruses, whereas a third gene family (‘beta-28’) is only found in primate CMVs. Unusual features exhibited by many of the herpesvirus GPCRs include constitutive signalling and constitutive endocytosis, whereas most cellular GPCR require triggering by external ligands.

Constitutive endocytosis

In mouse and rat CMV, the beta-78 family members (M78 and R78) are required for efficient replication in tissue culture. We recently demonstrated that M78 exhibits rapid, constitutive endocytosis, with evidence for internalisation via both clathrin-dependent and independent routes (Sharp et al 2009). We are currently determining M78 motifs responsible for directing endocytosis and determining whether rapid endocytosis is required for efficient virus replication.

Constitutive signalling

In mouse and rat CMV, beta-33 family members (M33 and R33) do not affect replication in tissue culture, but have a profound effect in vivo, with no replication in salivary glands, a major site of virus persistence and shedding. More recently, we reported evidence that M33 also contributes to efficient reactivation from latency (Cardin et al, 2009). Beta-33 and beta-28 family members have been found to exhibit constitutive signalling, with evidence for G protein-coupled and G protein-independent signalling pathways. We have recently demonstrated that constitutive, G protein –coupled signalling by M33 is required for replication in salivary glands in vivo (Case et al, 2008). We are currently determining the contribution of specific signalling pathways to the in vivo phenotypes and the critical cell types involved.

Functional complementation

The HCMV GPCR homologues US28 and UL33 exhibit constitutive signalling properties that are similar to those of M33. We are interested in determining whether the HCMV GPCR can functionally substitute for M33 during infection of mice.. If so, this will provide a valuable model system for testing anti-viral drugs active against US28 or UL33, which are already in development in other laboratories. We have successfully generated gmMCMV where the M33 coding sequence has been replaced by either UL33 or US28. We are currently determining whether the HCMV GPCRs are able to rescue the in vivo phenotypes identified for M33. If so, we will have a unique system for evaluation of HCMV gene function in vivo and the impact of anti-viral GPCR drugs. A secondary research theme concerns the impact of herpesvirus strain variation upon pathogenesis. Prior to relocating to UQ, my laboratory at the AHT demonstrated that natural variation of a single equine herpesvirus-1 gene was strongly associated with severe, neurological disease in field outbreaks (Nugent et al, 2006; Goodman et al, 2007). Future work will be investigating the impact of human herpesvirus strain variation upon clinical outcomes.

Principal collaborators:

Dr. Rhonda Cardin (Cincinnati Children’s Hospital, USA)
Prof. Mette Rosenkilde (University of Copenhagen, Denmark)
Dr. Thomas Kledal (INAGEN, Roskilde, Denmark)

Funded Projects: 

NHMRC Project 2010-2012
Functions of viral chemokine receptor homologues important for cytomegalovirus pathogenesis and latency
Total value of grant: $296,750 

Teaching: 

Virology (guest lecturer)