How do viruses infect replicate and proliferate in skin?

Supervisors: Dr Ryan O'Shaughnessy and Professor Judith Breuer

The cornified envelope is the principle component of the protective barrier in the skin epidermis, and the major barrier to viral infection, replication and propagation. Cells in the basal layer constantly divide and then undergo terminal differentiation, moving upwards to replace the shed epidermis (Candi et al., 2005). Epidermal tropic viruses, such as Human Papilloma Virus (HPV) and Varicella Zoster virus (VZV), are able to replicate and propagate on skin (Gershon et al., 2010; Akgul et al., 2006). Cutaneous HPV, commonly causes benign cutaneous lesions known as warts. Primary infection with VZV results in chickenpox, a generalized skin blistering rash.

Our recent data suggests that VZV and HPV infection has a profound effect on differentiating skin cells and hijacks the normal process of epidermal gene expression to generate a signature which resembles patterns of gene expression seen in warts on the case of HPV (O’Shaughnessy et al., 2007; Ekeowa-Anderson et al., 2012) and blisters in the case of VZV. We found that HPV and VZV infection altered skin cell differentiation and increased the expression of a number of the chymotrypsin-like Kallikrein proteases, which we hypothesis can digest key structural component of the epidermis which leads to defects in the ability of the cells to form a strong barrier and hence facilitates viral propagation.

In this project the student will investigate the mechanisms employed by the virus to up-regulation kallikreins in VZV and HPV infections. The student will also investigate how KLK6 up-regulation alters the epidermal structure to impair epidermal barrier function to allow for viral propagation, and to form warts and blisters. Finally the student will investigate if blockade of KLK function or of the mechanisms that lead to KLK overexpression can prevent the formation of blisters in a model of VZV infection and warts in a mouse model of HPV infection. During the course of their studies, the student will become experienced in a range of molecular biology and protein chemistry techniques, as well as the use of organotypic culture models and animal models, as well as getting exposure to next generation sequencing technologies and analysis.

Although the work proposed is completely basic science research, it involves the investigation of the mechanism that the HPV and VZV viruses use to successfully infect, replicate and propagate in skin. This will directly lead to the elucidation of molecular mechanisms that are necessary for these processes and in time, the potential for preventing these processes by novel drug interventions.

References:
1) Akgül B, Cooke JC, Storey A. HPV-associated skin disease. J Pathol. 2006 Jan;208(2):165-75.
2) Candi E, Schmidt R, Melino G. The cornified envelope: a model of cell death in the skin. Nat Rev Mol Cell Biol. 2005 Apr;6(4):328-40.
3) Ekeowa-Anderson A.L., Purdie J.K, Gibbon K, Byrne C.R., Arbeit J.M , Harwood C.A. and O’Shaughnessy R.F.L. AKT1 loss correlates with episomal HPV16 in vulval intraepithelial neoplasia, PLoS One. 2012;7(6):e38608.
4) Gershon AA, Gershon MD, Breuer J, Levin MJ, Oaklander AL, Griffiths PD. Advances in the understanding of the pathogenesis and epidemiology of herpes zoster. J Clin Virol. 2010 May;48 Suppl 1:S2-7.
5) O’Shaughnessy, R. F., B. Akgul, A. Storey, H. Pfister, C. A. Harwood, and C. Byrne. 2007. Cutaneous human papillomaviruses down-regulate AKT1, whereas AKT2 up-regulation and activation associates with tumors. Cancer Res. 67: 8207-8215