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Investigating the molecular biology of activation and regulation of innate immune receptors that survey the cytosol, using a variety of virus infection models including influenza A virus, HIV and other retroviruses, flaviviruses such as Zika virus, and herpes viruses.

Rehwinkel

About the Research

Virus infection triggers a multitude of immune responses. Detection of virus presence by the innate immune system is a crucial event and is mediated by receptors inside cells. These sensors of virus presence signal for the activation of innate immune genes, such as those encoding type I interferons. These cytokines then alert neighbouring, uninfected cells and induce the expression of hundreds of genes, many of which encode proteins with direct antiviral function. Viruses in turn have developed strategies to counteract and evade detection and control by the innate immune system. As such, cells and viruses are in a dynamic arms race in which host defence mechanisms and viral counter-measures rapidly co-evolve. Our aim is to understand the molecular basis of host pathogen interactions.

Nucleic acids are triggers for many innate immune responses. This is best understood in the context of virus infection. When viruses infect cells, their nucleic acids – such as viral DNA and RNA genomes, replication intermediates or viral transcripts – are detected by germ-line encoded receptors. These sensors of virus invasion then engage different signalling pathways to induce an antiviral state. This includes the production of interferons and other cytokines, stress responses and programmed cell death. Viruses cannot replicate and complete their life cycles without introducing their RNA or DNA genomes into host cells. Nucleic acid sensing is therefore a broadly effective cellular defence strategy for the detection of virus infection. However, the presence of vast quantities of cellular RNAs and DNAs in healthy, uninfected cells necessitates molecular mechanisms of self / non-self discrimination and poses the risk of unwanted immune responses in the absence of infection. Indeed, nucleic acid sensing pathways have been linked to autoinflammatory and autoimmune diseases. Moreover, nucleic acids are also involved in priming immune responses targeting cancers and are potent adjuvants for vaccination. The study of nucleic acid sensing is thus important to our understanding of host-pathogen interactions and the aetiology of some autoimmune diseases, and is likely to inform the development of novel therapies.

Our research focuses on the molecular biology of activation and regulation of innate immune receptors that survey the cytosol. We use a variety of virus infection models including influenza A virus, HIV and other retroviruses, flaviviruses such as Zika virus, and herpesviruses. In addition, we are studying the role of nucleic acid sensing in inflammatory diseases and in cancer. We are particularly interested in RIG-I-like receptors and cytosolic DNA receptors such as cGAS. Furthermore, we are interested in SAMHD1, which restricts virus infection and is also linked to Aicardi-Goutières syndrome – an autoinflammatory disease driven by interferons.

 

Training Opportunities

Based in the MRC Human Immunology Unit at the Weatherall Institute of Molecular Medicine, with access to state-of-the-art facilities, we provide an opportunity for training in a broad range of different techniques, including cell culture, molecular biology, immunology, virology and mouse models. Our work additionally benefits from close collaboration with many scientists. The successful candidate will be supervised by Jan Rehwinkel and additional day-to-day supervision will be provided by an experienced member of the Rehwinkel lab.

 

Students will be enrolled on the MRC WIMM DPhil Course, which takes place in the autumn of their first year. Running over several days, this course helps students to develop basic research and presentation skills, as well as introducing them to a wide-range of scientific techniques and principles, ensuring that students have the opportunity to build a broad-based understanding of differing research methodologies.

Generic skills training is offered through the Medical Sciences Division's Skills Training Programme. This programme offers a comprehensive range of courses covering many important areas of researcher development: knowledge and intellectual abilities, personal effectiveness, research governance and organisation, and engagement, influence and impact. Students are actively encouraged to take advantage of the training opportunities available to them.

As well as the specific training detailed above, students will have access to a wide-range of seminars and training opportunities through the many research institutes and centres based in Oxford.

All MRC WIMM graduate students are encouraged to participate in the successful mentoring scheme of the Radcliffe Department of Medicine, which is the host department of the MRC WIMM. This mentoring scheme provides an additional possible channel for personal and professional development outside the regular supervisory framework. The RDM also holds an Athena SWAN Silver Award in recognition of our efforts to build a happy and rewarding environment where all staff and students are supported to achieve their full potential.

 

Publications

Hertzog J, Dias Junior AG, Rigby RE, Donald CL, Mayer A, Sezgin E, Song C, Jin B, Hublitz P, Eggeling C, Kohl A, Rehwinkel J. Infection with a Brazilian isolate of Zika virus generates RIG-I stimulatory RNA and the viral NS5 protein blocks type I IFN induction and signaling. Eur J Immunol. 2018; 48(7):1120-1136.

Maelfait J, Liverpool L, Bridgeman A, Ragan KB, Upton JW, Rehwinkel J. Sensing of viral and endogenous RNA by ZBP1/DAI induces necroptosis. The EMBO Journal. 2017; 36(5):604-616.

Maelfait J, Bridgeman A, Benlahrech A, Cursi C, Rehwinkel J. Restriction by SAMHD1 limits cGAS/STING-dependent innate and adaptive immune responses to HIV-1. Cell Reports. 2016; 6:1492–1501.

Bridgeman A, Maelfait J, Davenne T, Partridge T, Peng Y, Mayer A, Dong T, Kaever V, Borrow P, Rehwinkel J. Viruses transfer the antiviral second messenger cGAMP between cells. Science. 2015; 349:1228-1232.

Rehwinkel J, Maelfait J, Bridgeman A, Rigby R, Hayward B, Liberatore RA, Bieniasz PD, Towers GJ, Moita LF, Crow YJ, Bonthron DT, and Reis e Sousa C. SAMHD1-dependent retroviral control and escape in mice. The EMBO Journal. 2013; 32:2454-2462.

Rehwinkel J, Tan CP, Goubau D, Schulz O, Pichlmair A, Bier K, Robb N, Vreede F, Barclay W, Fodor E, Reis e Sousa C. RIG-I detects viral genomic RNA during negative-strand RNA virus infection. Cell. 2010; 140:397-408.

Supervisors