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Nucleic Acid Sensing During Virus Infection – Innate Immunity


Weatherall Institute of Molecular Medicine

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Dr J Rehwinkel No more applications being accepted

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 are 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 ([Email Address Removed]).

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 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 also offered through the Medical Sciences Division’s Skills Training Programme and students will have access to a wide-range of seminars and training opportunities through the many research institutes and centres based in Oxford.



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 tuition and college fees paid and will receive a stipend of £18,000 per annum.

For October 2021 entry, the application deadline is 8th January 2021 at 12 noon midday, UK time.

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


References

RIG-I Plays a Dominant Role in the Induction of Transcriptional Changes in Zika Virus-Infected Cells, which Protect from Virus-Induced Cell Death. Schilling M, Bridgeman A, Gray N, Hertzog J, Hublitz P, Kohl A, Rehwinkel J. Cells. 2020 Jun 16;9(6):E1476.

SAMHD1 Limits the Efficacy of Forodesine in Leukemia by Protecting Cells against the Cytotoxicity of dGTP. 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. Cell Rep. 2020 May 12;31(6):107640.

Davenne T, Bridgeman A, Rigby RE, Rehwinkel J. Deoxyguanosine is a TLR7 agonist. Eur J Immunol. 2020; 50(1):56-62.
Rigby RE, Wise HM, Smith N, Digard P, Rehwinkel J. PA-X antagonises MAVS-dependent accumulation of early type I interferon messenger RNAs during influenza A virus infection. Sci Rep. 2019; 9(1):7216.

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.
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