The lab’s research projects are focused around the innate immune responses to virus infection in three main areas:
1) The innate immune response to viral nucleic acids.
Nucleic acids are powerful immunostimulatory agents. Sensing of damaged or mis-localised nucleic acids by pattern recognition receptors underlies multiple pathologies and is especially important in the context of anti-viral immunity. During DNA virus infection, the ability of our cells to sense viral genomic DNA it critical for mounting type one and type three interferon responses. We discovered that DNA-PK binds to cytoplasmic DNA and is required for the cGAS/STING pathway that drives the IRF-3 dependent production of interferons and cytokines in response to viral DNA. We are now are researching the intriguing links between the innate immune system and DNA damage response signalling pathways in response to DNA virus infections. In order to understand how nucleic acid sensing mechanisms evolved to drive anti-viral immunity we are taking a comparative immunology approach to define these mechanisms in multiple species including humans, mice and chickens
2) Vaccinology
There are many fundamental questions about the development of immunological memory which remain poorly understood. The initial detection of a vaccine vector by the innate immune system has long lasting consequences for the development of memory responses. We use vaccinia virus, the vaccine that was developed to eradicate smallpox to help understand these fundamental mechanisms of vaccinology. For example we have developed a panel of mutant viruses which have differential impacts on the development of lymphocyte memory. We have defined the impact of removing individual and multiple immunomodulatory proteins from vaccinia virus on vaccination responses and the generation of CD8 T cell memory
We are also working to understand the mechanisms by with vaccinia virus can generate such powerful memory immunity. We have recently discovered that vaccinia virus sabotages dendritic cell function and enters the draining lymph node to drive CD4 T cell activation, and that the pathology at the site of vaccination is almost completely dependent on opportunistic bacterial co-infection.
3) Linear ubiquitin chains in anti-viral immunity
Linear (or Met1) ubiquitin chains regulate multiple immune signalling pathways, especially those leading to NF-Kb activation. Linear ubiquitin chains are generated by the LUBAC complex which is recruited to many receptor signalling complexes, especially those implicated in inflammatory and cell death signalling. We have defined the contribution of LUBAC and M1 chains to anti-viral immunity via the RNA sensing pattern recognition receptors (PRRs), TLR3 and RIG-I in the context of influenza and Zika virus infection.
Collaborators:
Professor Daniel Mansur, University of Santa Catarina, Florianopolis, Brazil
Professor Geoffrey Smith, University of Cambridge, UK
Professor Henning Walczak, University College London, UK
Professor Steve Jackson, Gurdon Institute, Cambridge, UK
Dr Antonio Rothfuchs, Karolinska Institute, Stockholm, Sweden
Dr Tim Halim, Cancer Research Institute, Cambridge, UK
Professor Alan Melcher, Institute of Cancer Research, London, UK
Professor Kevin Harrington, Institute of Cancer Research, London, UK
Dr Rodrigo Guabiraba, INRA, Tours, France
Professor Clare Bryant, University of Cambridge, UK
Dr Yorgo Modis, University of Cambridge, UK
Dr Amanda Chaplin, Leicester University
Dr James Edgar, University of Cambridge, UK
Dr Rahul Roychaudhuri, University of Cambridge, UK
Dr Nerea Irigoyen, University of Cambridge, UK