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How does Vaccinia virus evade detection by the innate immune system?


Project Description

Background:
Most of our cells are able to detect when they have been infected by a virus. As part of the innate immune system, cells recognise hallmarks of infection such as the presence of DNA in the cytosol, to initiate a local immune response and alert neighbouring cells to the danger within the first hours of infection. Viral DNA can be detected by the cytosolic DNA sensor cGAS (cyclic GMP-AMP synthase), an enzyme which produces the second messenger cGAMP (cyclic GMP-AMP). cGAMP binds to the signalling adaptor STING (Stimulator of Interferon Genes), which then activates transcription factors to induce the production of interferons, cytokines and chemokines. These immune mediators initiate a local immune response, and help to establish an anti-viral state in neighbouring cells, preventing the spread of the virus throughout the body.

All viruses need to evade the innate immune system in order to establish an infection. Large DNA viruses, such as the poxvirus Vaccinia, encode many proteins that inhibit the host cell’s signalling cascades, in order to inhibit the innate immune response and remain undetected in the early stages of infection. We have recently discovered that a protein from Vaccinia virus causes the degradation of the DNA sensor cGAS immediately after infection of human skin cells. In this project, you will investigate how this viral protein functions, and how it synergises with other Vaccinia virus inhibitors of innate immune signalling.

Vaccinia virus was one of the original vaccines that contributed to the eradication of smallpox. Variants of the virus are now being developed as vaccine vectors for other diseases. Thus, the insights gained in this research project may lead to the rational design of vaccine vectors that are more immunogenic and safer to use.

Aims:
In this project, you will investigate how a Vaccinia virus protein causes the degradation of the DNA sensor cGAS in human cells, and test whether viruses lacking this immunomodulator induce a heightened immune response.

Methods:
This project involves a variety of molecular / cell biology techniques, at the interface of virology, immunology and cell signalling. You will grow human skin cells and infect them with viruses in culture, using category 2 biosafety facilities. The innate immune response in infected cells will be monitored using immunoblotting, confocal microscopy, real-time PCR and ELISA. You will also use immunoprecipitation and mass spectrometry approaches to probe the interactions between viral and host proteins. We will make use of recombinant viruses lacking immune evasion proteins to test their ability to activate the immune system.

Our laboratories have expertise in innate immune signalling and viral immune evasion (Almine et al., Nat Comms 2017; Dunphy et al., Mol Cell 2018; Santhakumar et al., Sci Rep 2018; Almine & Unterholzner, Immunology 2019, Unterholzner et al., PLOS Pathogens 2011).

The candidate
We are looking for a highly motivated candidate with a good understanding of immunology, virology and cell signalling, and an interest in host-pathogen interactions. Requirements are a good BSc or MSc, excellent communication skills and some relevant laboratory experience.

Funding Notes

Applications should be made directly to Dr Leonie Unterholzner: and should include:

CV (max 2 A4 sides), including details of two academic references
A cover letter outlining your qualifications and interest in the studentship (max 2 A4 sides)

References

Unterholzner L and Almine JF (2019). Camouflage and interception: How pathogens evade detection by intracellular nucleic acids sensors. Immunology, 156(3):217-227. Review.

Dunphy G et al. (2018). Non-canonical activation of the DNA sensing adaptor STING by ATM and IFI16 mediates NF-B signalling after nuclear DNA damage. Molecular Cell, 71(5):745-760.

Almine JF et al. (2017). IFI16 and cGAS co-operate in the activation of STING during DNA sensing in human keratinocytes. Nature Communications, 8:14392.

Unterholzner L (2013). The interferon response to intracellular DNA: Why so many receptors? Immunobiology, 218(11):1312-21.

Unterholzner L et al.(2011). Vaccinia virus protein C6 is a virulence factor that binds TBK-1 adaptor proteins and inhibits activation of IRF3 and IRF7. PLOS Pathogens 7(9):e1002247.

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