Research highlights

Dr Abendroth's team works on a medically important human herpesvirus, varicella zoster virus (VZV) infects up to 90% of the population. VZV causes chickenpox (varicella) predominantly in childhood and shingles (herpes zoster) in middle to old age people. Whilst VZV usually causes relatively mild disease in healthy individuals, VZV still causes significant morbidity in children and adults. VZV causes life-threatening disease in immunocompromised individuals such as patients who are elderly or have HIV disease. After recovery from chickenpox, VZV is not eliminated from the body but rather the virus has the remarkable ability to hide in the body in a dormant (latent) form in localized clusters of nerve cells (ganglia) for the life of the host. However, when conditions are right the virus can reawaken (reactivate) and cause shingles. This usually occurs in older people, and is characterized by a localized rash that can be very painful. The commonest and most widely feared complication of shingles is the severe, debilitating pain, referred to as post-herpetic neuralgia (PHN), that can persist for months or even years after the shingles rash has healed. Currently shingles cannot be prevented and there are no suitable treatments for shingles or PHN. Despite its significant impact on the community, little is known about the molecular details of how this virus functions.

Overview of research programme

The Varicella zoster virus (VZV) is the virus that causes chicken pox (Varicella), shingles (herpes zoster) and post-herpetic neuralgia (PHN). Chickenpox, which is usually seen in children is a clinical manifestation of primary (i.e. first time) infection with VZV and is highly contagious affecting the majority of the population. After recovery from chickenpox, VZV is not eliminated from the body but rather the virus has the remarkable ability to hide in the body in a dormant (latent) form in localized clusters of nerve cells (ganglia) for the life of the host. However, when conditions are right the virus can reawaken (reactivate) and cause shingles. This usually occurs in older people, and is characterized by a localized rash that can be very painful. The commonest and most widely feared complication of shingles is the severe, debilitating pain, referred to as PHN, that can persist for months or even years after the shingles rash has healed. Currently shingles can not be prevented and there are no suitable treatments for shingles or PHN.
Despite its significant impact on the community, little is known about the molecular basis of VZV infection, due in part, to VZV only infecting humans. To more closely examine the interaction of VZV with host cells, Dr Abendroth’s group has established several models of infection using human cell-types which are targets for infection and are relevant to those that suffer from either Varicella or herpes zoster/PHN because each of these cell types are likely to play different, but essential roles in the disease process. These include human fibroblasts (skin cells), neurons (nerve cells) and specialized immune cells (T cells and dendritic cells).

Interaction of VZV with human ganglionic cells

The group has shown that human nerve cells infected with VZV do not undergo programmed cell death (apoptosis). This is an important finding because it suggests the nerve cell damage observed when VZV reawakens from its "silent" state in nerve cells to cause shingles is not due to programmed cell death. Another implication from this observation is that VZV encodes a function to interfere with the death response in human nerve cells, thus providing a possible mechanism by which the virus can establish and maintain its life-long dormant infection. Dr Abendroth’s group went on to identify the first VZV encoded anti-apoptotic gene ORF63. To further our understanding of VZV with human nerve cells the group has developed and published a novel model of VZV infection of intact human explant ganglia. The group has shown for the first time that VZV can infect intact human ganglionic cells and this is a novel way of studying the interaction of this virus with human nerve cells.
The features of intact ganglionic infection can now be studied in further detail to better define the molecular mechanisms that underlie VZV infection of ganglionic cells. For example, this model provides a means to rapidly test viral gene mutant viruses and new candidate vaccine strains containing targeted gene disruptions to define viral genes that may play critical roles in VZV neurotropism and to examine in detail the outcome of infection of both neurons and non-neuronal cells with respect to apoptosis and cell function.
Significantly, we have now obtained rare naturally infected ganglia samples at autopsy from patients who suffered from herpes zoster close to the time of death, but who had died from unrelated causes. We are now uniquely placed to extend our earlier work by examining the interaction of VZV with ganglionic cells in both experimentally and naturally infected settings. These studies will be important for the development of better therapies to lessen the impact of VZV disease on the community.

Interaction of VZV with human dendritic cells (DCs)

Another major focus of the VZV Research laboratory is the interaction of the virus with human dendritic cells. There has been a tremendous new interest in DC as virus targets and in their role in antigen presentation and induction of both innate (NK cells via IFN) and adaptive cellular immunity. The skin is a major site of VZV replication yet it is also the site of immature DC (eg Langerhans cells) which sample the micro-environment for pathogens, and which are a pivotal cell type in the induction of anti-viral immune responses. The VZV lab has a major research focus on virus encoded immunomodulation and the infection and impact of VZV on human DCs. We were the first to show that VZV can infect immature and mature dendritic cells (DCs) and infection disrupts the ability of these cells to function properly in initiating an immune response. Thus, we have discovered that VZV has the ability to delay and/or evade the host immune system by infecting and altering the immune function of DCs.
Given the importance of the skin as a site of VZV infection and the role skin DC play in the induction of anti-viral immunity, there is good reason to study infection and modulation of DC in human skin during VZV infection. To date, we have determined the DC subsets that may participate in VZV pathogenesis by immunostaining sections of chickenpox and shingles skin lesions for immune cell markers. In VZV infected skin, Langerhans cells (LC), were decreased and plasmacytoid DC (PDC), DC that produces high levels of IFN-alpha, were increased in frequency compared to uninfected skin. We investigated whether these DC subsets support VZV infection in vivo by dual immunofluorescently staining sections of VZV infected skin lesions for LC/PDC markers and VZV proteins. Notably, a proportion of LC and PDC were positive for VZV proteins, suggesting these cells can be infected. Further assessment of skin DC infection, immune function and viability will define the mechanisms underlying cutaneous infection. These studies will enable a critical definition of the mechanistic basis of VZV modulation of host cell functions which is needed for development of a “second generation” vaccine to lessen the impact of VZV disease on the community.

Major funding sources

NHMRC project grant (2009-2011) Abendroth and Arvin.
Neuropathogenesis of varicella zoster virus infection.

Selected Publications

1. Abendroth, Kinchington, Slobedman (2010) Varicella zoster virus immune evasion strategies. Current Topics in Microbiology in Immunology. Editors Abendroth; Moffat; Arvin. Springer, Heidelberg, Germany. In press.
2. Steain, Slobedman, Abendroth (2010) Experimental models to study varicella zoster virus infection of neurons. Current Topics in Microbiology in Immunology. Eds Abendroth; Moffat; Arvin. Springer, Heidelberg, Germany. Epub April 1, 2010.
3. Huch, Cunningham, Arvin, Nasr, Santegoets, Slobedman, Slobedman, Abendroth (2010). Impact of varicella zoster virus on dendritic cell subsets in human skin during natural infection. Journal of Virology 84:4060-72.
4. Gowrishankar, Slobedman, Cunningham, Miranda-Saksena, Boadle, Abendroth (2007). Productive varicella zoster virus infection of cultured intact human ganglia. Journal of Virology. 81(12) 6752-6756.
5. Hood, Cunningham, Slobedman, Arvin, Sommer, Kinchington, Abendroth (2006). Varicella zoster virus ORF63 inhibits apoptosis of primary human neurons. Journal of Virology, 80(2) 1025-1031.
6. Ku, Besser, Abendroth, Grose, Arvin (2005). Varicella-Zoster virus pathogenesis and immunobiology: new concepts emerging from investigations of the SCID-hu mouse model. Journal of Virology, 79(5) 2651-2658.
7. Hood, Cunningham, Slobedman, Boadle and Abendroth (2003). Varicella zoster virus infected human sensory neurons are resistant to apoptosis yet human foreskin fibroblasts are susceptible: evidence for cell-type spescific apoptosis induced by VZV infection. Journal of Virology, 77: 12852-64.
8. Morrow, Slobedman, Cunningham & Abendroth (2003). Varicella zoster virus productively infects mature dendritic cells and alters their immune function. Journal of Virology, 77: 4950-4959.
9. Abendroth, Morrow, Cunningham & Slobedman (2001). Varicella zoster virus infection of human dendritic cells and transmission to T cells: Implications for virus dissemination in the host. Journal of Virology, 75: 6183-6192.
10. Abendroth, Lin, Slobedman, Ploegh & Arvin (2001). Varicella Zoster Virus Retains Major Histocompatibility Complex Class I Antigens in the Golgi of Infected Cells. Journal of Virology, 75: 4878-4888.
11. Abendroth, Slobedman, Lee, Wallace & Arvin (2000). Modulation of major histocompatibility class II expression by varicella zoster virus. Journal of Virology, 74: 1900-1907.

Major collaborations

1. Professor Ann Arvin, Stanford University School of Medicine, USA
2. Professor Tony Cunningham (AO), Westmead Millennium Institute, University of Sydney.
3. Associate Professor Barry Slobedman, Centre for Virus Research, Westmead Millennium Institute, University of Sydney
4. Dr Michael Rodriguez, Dept Forensic Medicine, Sydney South West Area Health Service.
5. Dr Michael Buckland, Dept Pathology, University of Sydney.
6. Prof Peter Blumbergs, Dept Pathology, Institute of Medical and Veterinary Science.
7. Associate Professor Paul Kinchington, Dept Opthamology, University of Pittsburgh, USA.
8. Professor Karin Petersen, Pain Clinical Research Centre, University of California, San Francisco USA.
   Dr Saskia Santegoets, Department of Pathology, VU University Medical Center, VU University, Netherlands.