Centre for Perinatal Infection Research
||Associate Professor . Cheryl A Jones MBBS PhD FRACP (Paeds)
||Senior Lecturer and Sub Dean Postgraduate Studies (Disc. of Paediatrics & Chid Health, University of Sydney). Paediatric Infectious Diseases Consultant & Head, Perinatal Infection Research (The Children's Hospital at Westmead).
Summary of Unit
The Perinatal Infection Research Unit (the Herpesvirus Research Unit) was established at The Children’s Hospital at Westmead in 1999 by Dr. Jones. Our research work addresses the significant clinical problem of infections acquired by the fetus and newborn through maternal infection (congenital and perinatal infections). These infections also contribute to a large burden of disease and disability and a large but unmeasured burden of miscarriages, stillbirths, and premature births. Our overall research objective is to reduce this by directing antenatal and postnatal interventions.
Major research achievements of the Unit over the past 5 years have included the demonstrate that:
- The newborn to mount a reduced cytotoxic T cell response to herpes simplex virus.
- Newborn dendritic cells display impaired ability to activate T cells (using novel technologies that track the induction of the newborn antiviral response in vivo).
- Herpes simplex virus (HSV) causes programmed cell death (apoptosis) of dendritic cells, the first immune cell to contrast the virus, in contrast to its effect on virtually every other cell type studied.
- Australia has a large burden of medically important congenital and perinatal infections that are not recorded by Federal reporting systems (e.g. HSV, cytomegalovirus- CMV, hepatitis C virus) using de-identified national surveillance.
- Newborn primary T cell responses to HSV are suppressed by enhanced regulatory T cell activity.
Aims of Unit
Our research focus is to determine the reasons why the immune system of a newborn infant does not protect them against certain viral infections, like herpes simplex virus (HSV) or cytomegalovirus (CMV). These viruses can cause devastating disease if infection occurs in utero or in the first weeks of life, but mild to no disease in older children or adults. We ultimately want to develop ways to prevent these infections in the very young and improve upon the treatment options available to this age group. We also perform internationally recognised national surveillance of these medical important infections that occur before at around the time of delivery (i.e. congenital and perinatal infections) to define the burden of disease caused by these infections in Australian children. These studies will allow us to rationally implement the preventative strategies we develop in a cost effective manner.
* Neonatal antiviral immunity
Our laboratory has developed a unique murine model of neonatal HSV infection that has led to a series of major findings and collaborative studies including that maternal vaccination against herpes simplex virus may prevent spread to the organs but not to the brain (Journal of Infectious Diseases, 2002), and that the newborn have defective cytotoxic T cell responses to HSV in vitro (Evans & Jones, European Journal of Immunology, 2005). Extension of this work using novel assays in the live mouse (in collaboration with Prof. Frank Carbone Uni. Of Melbourne) has revealed that newborn mice mount their primary cytotoxic T cell response with delayed kinetics, reaching adult levels at approximately 2 weeks of age (Fernandez, Evans, Carbone & Jones, in preparation). Jones, C.A., Taylor, T.J., & Knipe, D.M. (2000). Biological properties of herpes simplex virus 2 replication-defective mutant strains in a murine nasal infection model. Virology, 278, 137-150.
* The dendritic cell responce to viruses
Our laboratory (in collaboration with Prof., Tony Cunningham, WMI). has also made the novel finding that HSV infection of cultured dendritic cells, the immune cell required to switch on naďve T cells, significantly impairs their function, and induces them to undergo programmed cell death (apoptosis) in contrast to HSV infection of virtually every other cell type (Journal of Virology, 03). Elucidation of the mechanism of this response is ongoing.
* The role of regulatory T cells in newborn antiviral T cell responses
Regulatory T cells (Tregs) control autoimmunity and excessive immune responses to infection. We have recently demonstrated that there is a small, but significant increase in the frequency of Tregs in the draining LN of HSV infected neonatal mice and that depletion of these cells prior to HSV infection significantly enhances CD8+ T cell responses and reduces the amount of virus in the lymph nodes and brain. These studies support the notion that the newborn primary T cell responses to HSV are suppressed by Treg activity. Studies to define the mechanism of Treg inhibition of antiviral responses are underway.
* National surveillance for congenital and perinatal infections
The Unit is running three collaborative studies of national surveillance of congenital/perinatal infections through the Australian Paediatric Surveillance Unit (HSV, Hepatitis C virus, Rubella from 2004), and collaborating on a fourth (atypical mycobacterium) and have a fifth protocol that will start in mid 2008 (congenital toxoplasmosis). These studies have provided unique information on the burden of disease and epidemiology of these rare but important infections. These data will be vital in the implementation and evaluation of any preventative strategies such as vaccines.
* Cochrane reviews of antiviral agents
We have completed a systematic review with the Renal Cochrane collaboration Centre for Kidney Research, CHW on Antiviral agents to prevent CMV disease in solid organ transplant recipients. This protocol has been published in the current edition of the Cochrane library, and some of the results have been published in 2005 (Hodson, Jones et al, Lancet 2005, Transplantation, 2005). We are also undertaking reviews of antiviral agents with the Neonatal Cochrane review team for the treatment of neonatal HSV disease and for the treatment of symptomatic congenital CMV infection in infants up to 3 months of age. These protocols are published in the Cochrane library.
* Antenatal and postnatal predictors of poor clinical outcome in infants with congenital CMV infection
In collaboration with A/Prof. Rawlinson’s group, at the University of New South Wales, we are currently investigating antenatal and postnatal predictors for adverse outcome in infants with congenital CMV infection. The project has recently funded by the SIDS4KIDS foundation.
- Dr. Marian Fernadez - Senior Postdoctoral Fellow
- Mr. Franz Puttur - PhD Student
- Mr. Eddy Hassan - Master Science in Medicine Student
- Ms. Meera Esvaran - Research Assistant
- Ms. Maggie Brett - Hospital Scientist
Jones CA. Infections in the critically Ill Neonate. In:" Infectious Diseases in the Pediatric Intensive Care Unit." Simon Nadel & Brett Giroir, Eds. Springer-Verlag (London). 2007. In press, February 7, 2007.
Hodson EM, Jones CA, Strippoli GF, Webster AC, Craig JC. Immunoglobulins, vaccines or interferon for preventing cytomegalovirus disease in solid organ transplant recipients.Cochrane Database Syst Rev. 2007;(2):CD005129
Hodson EM, Strippoli GFM, Jones CA, Vimalchandra D, Craig JC. Pre-emptive treatment for cytomegalovirus viraemia to prevent cytomegalovirus disease in solid organ transplant recipients: A systematic review of randomised clinical trials. Transplantation 2006; 81: 139- 145.
Hardikar W, Elliott E, Jones CA. The silent infection: should we be testing for perinatal hepatitis C and, if so, how? Med J Aust 2006; 184: 54-55.
Cunningham AL, Diefenbach RJ, Miranda-Saksena M, Bosnjak L, Kim M, Jones C, Douglas MW. Related Articles, Links Abstract The cycle of human herpes simplex virus infection: virus transport and immune control. J Infect Dis. 2006;194 Suppl 1:S11-8.
D Isaacs, CA Jones, D Dalton, T Cripps et al. Exposure to open tuberculosis on a neonatal unit. Journal of Paediatrics & Child Health. 2006;42:557-9.
Bosnjak L, Miranda-Saksena M, Koelle DM, Boadle RA, Jones CA, Cunningham AL. Related Herpes simplex virus infection of human dendritic cells induces apoptosis and allows cross-presentation via uninfected dendritic cells. J Immunol. 2005;174(4):2220-7.
IA Evans, Jones CA. HSV-2 induces a short lived, early primary Th-1 CD4 T cell response in neonatal mice, but no cytotoxic effector activity. Eur J Immunol 2005; 35: 1454-1462
Hodson EM, Jones CA, Strippoli GFM, Vimalchandra D, Craig JC. Antiviral therapy to prevent cytomegalovirus viraemia to prevent cytomegalovirus disease in solid organ transplant recipients: A systematic review of randomised controlled trials. The Lancet. 2005; 365: 2105-2115.
Hodson EM, Strippoli GFM, Jones CA, Vimalchandra D, Craig JC (In Press) Pre-emptive treatment for cytomegalovirus viraemia to prevent cytomegalovirus disease in solid organ transplant recipients: A systematic review of randomised clinical trials. Transplantation, 2005.
Fernandez MA, Evans IE, Carbone F, Cunningham A, Jones CA. Under Review, Journal of Immunology.
Bosnjak L, Abendroth A, Jones CA, Cunningham AL (In Press) Dendritic cell biology in herpesvirus infections. Invited review. Viral Immunology, September 2005.
Mindel, A. Freidman E, Jones CA, Prevention of neonatal herpes. Herpes, 2004. 11; 38-40.
Jones CA, Isaacs D. Management of herpes simplex virus infections in childhood. Current Paediatrics, 2004:14;131-136.
Jones CA, Cunningham AC. Vaccination strategies to prevent genital herpes and neonatal herpes simplex virus (HSV) disease. Herpes, 2004 ;11:12-7.
Jones CA. Vaccines to prevent neonatal herpes simplex virus infection. Exp. Rev. Vaccines3 (4): 363-4.
This document was reviewed on Wednesday, 1 August 2007