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Nucleic Acid Sensing During Virus Infection


   Weatherall Institute of Molecular Medicine

   Friday, December 03, 2021  Competition Funded PhD Project (Students Worldwide)

Oxford United Kingdom Biochemistry Cancer Biology Genetics Immunology Microbiology Molecular Biology Virology

About the Project

Virus infection is a constant threat to the cells of all living organisms. To counter this threat, cellular receptors detect virus presence and activate potent antiviral immune responses. Some of these sensors of virus presence signal for the activation of innate immune genes, which in humans include 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 investigate the molecular mechanisms by which mammalian cells recognise and respond to infection by viruses.

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. Nucleic acid sensors engage different signalling pathways to induce an antiviral state. This includes the production of interferons and other cytokines, stress responses and programmed cell death. 

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, herpesviruses and SARS-CoV-2. 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 – and cancer. Some of the projects in our lab look at: 

1. How cGAMP is packaged into viral particles to trigger antiviral immunity upon infection, and if this can be used to enhance vaccine responses.  

2. How unusual DNA and RNA molecules in the Z-conformation, a possible by-product of viral infection, are sensed by ZBP1 and other proteins in the innate immune system.

3. The mechanisms by which the Zika Virus, Varicella Zoster Virus and SARS-CoV-2 are detected by the innate immune system, and how these viruses counteract detection.

Jan Rehwinkel would be delighted to discuss these and related projects further with shortlisted candidates, who should make contact via email upon invitation to interview ().

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 (who recently won the Andrew McMichael Medal for excellent graduate supervision) at weekly 1-to-1 meetings. Additional day-to-day supervision will be provided by an experienced member of the Rehwinkel lab. The successful candidate will also present on a weekly basis at laboratory meetings and will expand their knowledge of the field through a regular journal club. Jan Rehwinkel is highly supportive of students’ career development and encourages students to attend and participate in scientific conferences.

Students will be enrolled on the MRC Weatherall Institute of Molecular Medicine 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.

The Department has a successful mentoring scheme, open to graduate students, which provides an additional possible channel for personal and professional development outside the regular supervisory framework. We hold 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.


Funding Notes

Funding for this project is available to scientists through the WIMM Prize Studentship and the RDM Scholars Programme, which offers funding to outstanding candidates from any country. Successful candidates will have all fees paid and will receive a stipend.

For October 2022 entry, the application deadline is 3rd December 2021 at 12 noon midday, UK time.

Please visit our website for more information on how to apply.

References

1 Sampaio NG, Chauveau L, Hertzog J, Bridgeman A, Fowler G, Moonen JP, Dupont M, Russell RA, Noerenberg M, Rehwinkel J. The RNA sensor MDA5 detects SARS-CoV-2 infection. Sci Rep. 2021; 11(1):13638.
2 Tang Q, Rigby RE, Young GR, Hvidt AK, Tan TK, Bridgeman A, Townsend AR, Kassiotis G, Rehwinkel J. Recognition of Z-RNA by ADAR1 limits interferon responses. bioRxiv 2020.12.04.411793.
3 Hertzog J, Rigby RE, Cursi C, Davenne T, Rehwinkel J. Varicella-Zoster virus ORF9 is a novel antagonist of the cytosolic DNA senor cGAS. bioRxiv 2020.02.11.943415.
4 Davenne T, Klintman J, Sharma S, Rigby RE, Blest HTW, Cursi C, Bridgeman A, Dadonaite B, De Keersmaecker K, Hillmen P, Chabes A, Schuh A, Rehwinkel J. SAMHD1 limits the efficacy of forodesine in leukaemia by protecting cells against cytotoxicity of dGTP. Cell Reports. 2020; 31(6):107640.
5 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.
6 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.

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