How do herpes simplex viruses interact with dendritic cells in human skin: clues for vaccine development

Summary

Herpes Simplex Virus (HSV) can cause cold sores, genital herpes, keratitis, encephalitis and neonatal herpes. 70-80% of human population is infected with HSV-1 and 22% with HSV-2. Once it infects the human body, it persists throughout life. HSV infection increases the acquisition of HIV by 2-3 fold. There is no vaccine available yet.

Understanding the interaction between HSV infection of genital skin/mucosa and its interactions with skin dendritic cells (DCs) is of key importance in elucidating how HSV specific CD4 and CD8 lymphocytes are activated and home to the infected lesion and persist at the site of infection between lesions to eradicate infection.

It is now known that the interaction between various classes of DCs in the skin is required for this process. Initially it was thought that HSV infection of Langerhans cells (LCs) led to migration of these cells to lymph node and to stimulation of CD4 and CD8 lymphocyte responses there. From the work of Carbone/Heath and our own laboratory we now know that HSV infects Langerhan cells in the epidermis which results in transfer to dermal DCs which exit from the dermis and then travel to lymph node. However, such direct interactions between LCs and dermal DCs has never been visualised or studied and these processes are only known in mice. We have developed a unique model of HSV infected human foreskins which shows the direct interaction between HSV infected epidermal LCs and dermal DCs.

This NHMRC funded study will give insight on fundamental understanding of how innate and adaptive immune cells in skin epidermis and dermis cooperate to eliminate HSV and may contribute to development of HSV vaccine candidates.

These fundamental processes are of great importance in developing vaccine candidates for HSV which have implications also for HIV and the development of novel vaccines in adjuvants.

Supervisor(s)

Professor Tony Cunningham, Dr Min Kim

Research Location

Westmead - Westmead Millennium Institute

Program Type

PHD

Synopsis

1. Examine migration of infected Langerhan cells out of epidermis and through basement membrane (initially confocal microscopy fluorescence).
2. Examine interaction of HSV infected Langerhans Cells with dermal DCs
- Determine whether they form polarised interactions after migration
- Is there phagacytosis?
3. Examine immigration of blood DCs into dermis, e.g. the BDCA3+ subset of DCs from dermal capillaries into HSV infected skin.
4. Examine effects of specific chemokines such as interleukin 8 on BDCA3+ dermal DC immigration from capillaries to dermis (without HSV infection).
5. Examine inhibitors of interaction with these chemokines and their receptors on HSV induced immigration of BDCA3+ DCs into dermis
6. What is the mechanism which drives HSV infected LCs to contact DCs? (possible chemokine driver).
7. Determine whether exogenous resting or activated CD4 or CD8 T cells can infiltrate into human skin explants responding to topically inoculated HSV or HSV antigens or chemokines.
8. To determine whether CD8 lymphocytes activated by HSV antigen in vitro are attracted into HSV infected explants and whether this is due to the chemokines CXCL9 and 10 (using inhibitors of the latter).
9. Examine the interaction between residential or infiltrated CD4 or CD8 T cells and dermal DCs infected or not with HSV.

Additional Information

This is a scholarship open to both domestic and international students.

Student Training
The successful PhD student will obtain a thorough grounding in innate and adaptive immunity to viral pathogens and skills in, skin expalnt process/culture, primary cell culture, virus culture, immune cell isolation using density gradient centrifugation and microbeads, flow cytometry, immunofluorescent microscopy, immunoassay such as ELISA and intracellular cytokine assay and molecular studies of cytokines and chemokines.

Applications

Dr Min Kim
Westmead Millennium Institute
PO Box 412
WESTMEAD NSW 2145
T: 9845 5583
F: 9845 9100

Closing Date 28 February 2013

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Keywords

Dendritic cells, herpes simplex virus, Langerhan cells, skin

Opportunity ID

The opportunity ID for this research opportunity is: 1663

Other opportunities with Professor Tony Cunningham

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