– — Virology Research Laboratory

PROJECTS IN VIROLOGY COMMENCING 2019

Projects in the Virology Research Laboratory are available in basic and applied molecular and cellular virology, funded by the NHMRC, ARC, and charitable grants. They involve training in molecular methods, protein chemistry, statistics and genomic analysis.

Honours and PhD projects are internationally competitive and align with the student’s research interests. The Honours projects provide a solid foundation for extension into a research project for those seeking to undertake a PhD. We encourage you to visit the laboratory to meet with us, and discuss potential projects in more detail.

Program 1: CMV pathogenesis, placental infection and adverse pregnancy outcomes

Project leader: Dr Stuart Hamilton, T: 9382 9096 Stuart.Hamilton@health.nsw.gov.au

During pregnancy, human cytomegalovirus (CMV) can infect the placenta, and the developing fetus, resulting in congenital CMV illness. There are ~2000 Australian infants born each year with congenital CMV infection, and ~10% develop symptoms including sensorineural hearing loss and mental disability. Understanding pathogenesis of CMV infection is critical for developing more effective treatments for congenital CMV. These studies investigate pathways of CMV-induced placental damage, transplacental transmission, and factors influencing disease outcome. We have discovered CMV modulates signaling pathways involved in placental development and are now further characterizing these changes in experimental models of human primary placental cells, which allow experiments that are not possible in pregnant women. Ultimately this work aims to prevent congenital CMV.

Selected articles:

Rawlinson WD, Boppana SB, Fowler KB, Kimberlin DW, Lazzarotto T, Alain S, Daly K, Doutré S, Gibson L, Giles ML, Greenlee J, Hamilton S, Harrison GJ, Hui L, Jones CA, Palasanthiran P, Schleiss MR, Shand AW, and van Zuylen WJ (2017) Congenital Cytomegalovirus Infection in Pregnancy and the Neonate: Consensus Recommendations for Prevention, Diagnosis, and Therapy. The Lancet Infectious Diseases March 10.
van Zuylen WJ, Ford CE, Wong DY, Rawlinson WD (2015) Human Cytomegalovirus Modulates Expression of non-canonical Wnt receptor ROR2 to Alter Trophoblast Migration. J Virol. Nov 11;90 (2):1108-15.

Program 2: Novel antiviral strategies to treat human cytomegalovirus infection. 1-2 places

Project leaders: Prof Bill Rawlinson T: 9382 9113, w.rawlinson@unsw.edu.au; Dr Stuart Hamilton, T: 9382 9096, Stuart.Hamilton@health.nsw.gov.au

Despite the enormous clinical and social importance of congenital CMV, there are currently no licensed therapeutics available for the treatment of CMV infection during pregnancy. This is due to limited evidence for antiviral efficacy and associated drug toxicity to the developing fetus. We have established an ex vivo human placental model system to simulate placental development and function during pregnancy. In collaboration with international partners, this project is investigating the safety and efficacy profiles of novel CMV antiviral compounds in cell culture and placental explant models. These studies will guide future directions in therapeutic development in both congenital CMV and transplantation settings.

Selected articles:

Hutterer C, Hamilton ST, Steingruber M et al. (2016) The chemical class of quinazoline compounds provides a core structure for the design of anticytomegaloviral kinase inhibitors. Antiviral Research doi:10.1016/j.antiviral.2016.08.005
Hamilton ST, van Zuylen W, Shand A, Scott G, Naing Z, Hall B, Craig M, Rawlinson WD (2014) Prevention of congenital cytomegalovirus complications by maternal and neonatal treatments: a systematic review. Reviews of Medical Virology 24:420-433
Hamilton ST, Scott G, Naing Z, Iwasenko J, Hall B, Graf N, Arbuckle S, Craig ME, Rawlinson WD (2012) Human cytomegalovirus induces cytokine changes in the placenta with implications for adverse outcomes. Plos One 7(12): e52899

Program 3: Virome and type 1 diabetes. 1 place available

Project leaders: Prof Maria Craig T: 9113 3637, m.craig@unsw.edu.au; Dr Ki Wook Kim T: 9382 9096 k.w.kim@unsw.edu.au

Type 1 (insulin-dependent) diabetes (T1D) is increasing in childhood and we do not know why. The rise has occurred rapidly, particularly among children without a family history of T1D. This strongly supports the major contribution of environmental factors in T1D aetiology. Viruses have been identified as prime environmental triggers of islet autoimmunity (IA) due to their strong molecular and epidemiological associations with T1D. Extensive research by us and others have clearly demonstrated the involvement of enteroviruses in the pathogenesis of T1D. In stark contrast, very few studies have examined the relationship of other virus infections to T1. Using cutting-edge Next Generation Sequencing techniques, this study will investigate the “virome” (entire population of viruses) in children who are at risk of developing T1D, participating in the nation-wide ENDIA cohort study (www.endia.org.au). Furthermore, the virome of pancreatic donor tissues collected by the Network for Pancreatic Donors with Diabetes (nPOD; https://www.jdrfnpod.org) will be investigated. Data resulting from this work is anticipated to facilitate future development of vaccines to prevent all viral causes of T1D.

Selected articles:

Allen DW, Kim KW, Rawlinson WD, Craig ME (2018) Maternal virus infections in pregnancy and type 1 diabetes in their offspring: systematic review and meta-analysis of observational studies. Reviews in Medical Virology, 22:e1974. doi: 10.1002/rmv
Phillips JE, Couper JJ, Penno MA, & Harrison L and ENDIA Study Group (2016) Type 1 diabetes: a disease of developmental origins. Pediatric Diabetes. doi:10.1111/pedi.12425
Briese T, Kapoor A, Mishra N, Jain K, Kumar A, Jabado OJ, Lipkin WI (2015) Virome Capture Sequencing Enables Sensitive Viral Diagnosis and Comprehensive Virome Analysis. mBio, 6:e01491-01415
Penno M, Couper J, Craig M, Colman P, Rawlinson WD, Cotterill A, Jones T, Harrison L and ENDIA Study Group (2013) Environmental determinants of islet autoimmunity (ENDIA): a pregnancy to early life cohort study in children at-risk of type 1 diabetes. BMC Pediatrics, 13:124
Yeung G, Rawlinson WD, Craig ME (2011) Enterovirus Infection and Type 1 Diabetes Mellitus – A systematic review of molecular studies. British Medical Journal, 342:d35 doi:10.1136/bmj.d35 2011

Program 4: Molecular mechanisms for enterovirus induced ?-cell lysis. 1 place available

Project leaders: Prof Maria Craig T: 9113 3637, m.craig@unsw.edu.au; Dr Ki Wook Kim T: 9382 9096 k.w.kim@unsw.edu.au

Enterovirus (EV) infection is a major environmental factor in the aetiology of T1D. Little is known about the mechanisms by which these viruses induce apoptosis and/or functionally impair pancreatic b-cells. Previously, we have shown that EV infection induces cytokine and chemokine production by b-cells and alters the abundance of microRNAs that are important for immune response to viral infection and cell signaling pathways. Currently, we are using Next Generation Sequencing and EV-infected human pancreatic islets to investigate the intra-host evolution of EVs during infection and how it may contribute to the establishment of viral persistence – a candidate mechanism via which EVs may induce prolonged b-cell dysfunction and autoimmunity. This project will apply a wide range of molecular and cell culture techniques.

Selected articles:

Isaacs SR, Wang J, Kim KW, Yin C, Zhou L, Mi QS, Craig ME (2016) MicroRNAs in Type 1 Diabetes: Complex Interregulation of the Immune System, beta Cell Function and Viral Infections. Current Diabetes Reports, 16:133
Kim KW, Ho A, Alshabee-Akil A, Hardikar AA, Kay TWH, Rawlinson WD and Craig ME (2016) Coxsackievirus B5 Infection Induces Dysregulation of microRNAs Predicted to Target Known Type 1 Diabetes Risk Genes in Human Pancreatic Islets. Diabetes, 65(4), 996-1003. doi:10.2337/db15-0956
Thomas H (2016) Diabetes: Enterovirus dysregulates islet miRNAs. Nature Reviews Endocrinology, 12:2-2

Program 5: Respiratory Viruses. 1 place available

Project leader: Dr Sacha Stelzer-Braid, 9382 9096, s.stelzer-braid@unsw.edu.au

Respiratory viral infections are a common cause of illness and an important cause of morbidity and mortality in the community. Current diagnostic testing for respiratory viruses is by polymerase chain reaction, which is sensitive, although typical turn-around-time to diagnosis is approximately one day. Using rapid “point-of-care tests” (POCT) tests can result in the reduced length of hospital stay and increased antiviral prescription patients with influenza. Recent developments of new version POCT have a turn-around-time of around 30 min, and are highly sensitive and specific for influenza and other respiratory viruses. We are using these POCT in different cohorts to measure improvement in patient outcomes.

Selected articles:

Stelzer-Braid S., Liu N., Doumit M., D’Cunha R., Belessis Y., Jaffe A., Rawlinson W.D. (2017) Association of rhinovirus with exacerbations in young children affected by cystic fibrosis: Preliminary data. Journal of Medical Virology, doi: 10.1002/jmv.24794.
Homaira N., Sheils J., Stelzer-Braid S., Lui , Oie J-L., Snelling T., Jaffe A. and Rawlinson W. (2015) Respiratory syncytial virus in the neonatal intensive care unit. Journal of Medical Virology, 88(2):196-201.
Stelzer-Braid S., Tovey E.R., Willenborg C.M., Toelle B.G., Ampon R., Garden F.L., Oliver B.G., Strachan R., Belessis Y., Jaffe A., Reddel H.K., Crisafulli D., Marks G.B. and Rawlinson W.D. (2015) Absence of back to school peaks in human rhinovirus detections and respiratory symptoms in a cohort of children with asthma. Journal of Medical Virology, 88(4):578-87

Program 6: Transmission risk of HBV from HBcAb positive donors through organ transplantation. 1 place available

Project Leader: Dr Vidiya Ramachandran, 93829135, vidiya.ramachandran@health.nsw.gov.au

This project will investigate the potential for transmission of hepatitis B virus (HBV) through organs from donors who have HBV positive serological markers, specifically hepatitis B core antibody (HBcAb). The risk appears to differ according to the organ implanted, being very high in the case of the liver and low for the rest of organs. However, the final confirmation of the suitability of using HBcAb positive donors in organ transplants is the absence of viral transmission to recipients. Our studies are of the prevalence of these donors in the Australian population, whether or not sero-conversion and/or positive HBV DNA results have appeared among the recipients, the likelihood of HBV transmission through different organs, and the optimum therapy for these recipients

Selected articles:

Martinez M, Kok C, Baleriola C, Robertson P, Rawlinson WD (2015) Investigation of occult hepatitis B virus infection in anti-HBc positive patients from liver clinic. PLoSone 2015. 10(3):e0117275
Baleriola C, Tu E, Johal H, Gillis J, Ison MG, Law M, Coghlan P, Rawlinson WD. Organ donor screening using parallel nucleic acid testing allows assessment of transmission risk and assay results in real time. Transpl Infect Dis. 2012 .14(3 ) 278 – 287