The 8^th Annual IITM Symposium took place this past November, which has always been an excellent opportunity for all IITM students to showcase their research. The symposium allowed students from all years of the programme to discuss their research, receive feedback, and begin considering their future career paths with the help of two fantastic keynote speakers. This year, keynote presentations were given by former IITM alumni Dr Rosanna McEwen-Smith, who discussed her success as a senior scientist at Adaptimmune, and Dr Chris van Tulleken, a former Oxford graduate in medicine and current BBC television presenter.

2018 IITM Symposium – St Edmund Hall. Photographer: Gillman & Soame

This year, talks from 3^rd and final year students were interwoven and divided into four sessions, and 2^nd-year students gave 3-minute lightning talks which preceded a poster-session to showcase their preliminary findings and research plans in greater depth.

From our 4^th year students, we were excited to hear about the progress on projects nearing their final stages. Richard described the involvement of regulatory T cells and pro-/anti-inflammatory cytokines in malarial immunity, and Layal described her progress in establishing a novel screening assay for viral antagonists of ZBP-1. Cherrelle then described the contribution of HIV-1-infected macrophages in pathogenesis of HIV-1-associated inflammation through analysis of cytokine-expression patterns. Hannah provided us with insight on protein antibiotic pyocin S5, and how its potency may be key in tackling Pseudomonas aeruginosa infections.

On the big data front, Lucy debriefed us on her analysis of RNA-seq and ATAC-seq to uncover the unique phenotype and function of mucosal-associated invariant T cells, and Marianne provided an update to her analysis of how Neisseria commensals acquired polysaccharide capsules through horizontal gene transfer. Finally, Meg showed us the exciting use of RNAseq in studying trypanosomatid parasite infection in her model organism Drosophila melanogaster.

With several breaks in-between the talks to re-fuel, we heard presentations from 3^rd year students, who have all made significant progress into their projects since selecting their labs last year. Rob showed us his progress in the design of adeno-associated capsids for greater antigen diversity, and Juliane gave us a look into her work on ER α-glucosidase I and the search for specific enzyme inhibitors. Felix described a model of adipocyte-specific autophagy in mice to uncover the immunobiology of free fatty acids, and Alun presented his findings on the role of cyclophillins in macrophages using CRISPR technology and stem cell-derived macrophages. Last, but not least, Johannes described his work in improving our understanding of T cell activation through involvement of accessory receptors which enhances sensitivity of antigen recognition.

Lightning talks from our 2^nd year students turned out to be extremely effective in summarizing the goals of their projects over the next couple of years, and the poster session allowed them to receive invaluable feedback from both faculty and peers. We look forward to hearing their progress next year!

The symposium concluded officially with two keynote speeches – the first from Dr. Rosanna McEwen-Smith, who described her successful transition from academia to industry as a current Senior Scientist at Adaptimmune, a T cell therapy-based biotech firm based in Abingdon. An IITM graduate from the Cerundolo lab, Rosanna attributed her success to the knowledge she gained about T cells over the course of her DPhil, and acquisition of numerous transferable skills which are now applicable to the managerial aspects of her career. We were extremely grateful the sharing of her experiences job-hunting after her DPhil, and we gained important insight into how academia differs from industry. We thank Rosanna for lending us her time and giving us the opportunity to ask about her journey.

Dr. Chris van Tulleken, Source: vantullekenbrothers.com

The last presentation of the day came from Dr. Chris van Tulleken, who previously studied medicine at Oxford, and then completed a PhD at UCL. Since his studies, he has regularly presented BBC documentaries about health and medicine, with the goal of public education. He shared with us the curious effects of cold-water swimming as a treatment for depression, and a then-unpublished study about the promotion of infant formulas which are fueled by commercial interests and financial conflict. Charismatic and animated, Chris’ passion for science communication and his talents in story-telling left us in awe of how we can translate our academic careers into an unusual yet rewarding career in the media.

To conclude, we would like to extend a big thank you to our organizers this year, Hannah Behrens, Marianne Clemence, Cherrelle Dacon, Lucy Garner, Layal Liverpool and Richard Morter, for all their hard-work and dedication in making this a fantastic symposium.

Group photograph above has been reproduced by kind permission of Gillman & Soame photographers and can be ordered by visiting http://www.gillmanandsoame.co.uk using the Login 352246 and Password 154329.

Warmest congratulations to Corinna Kulicke, who recently passed her DPhil viva. Corinna was supervised by Paul Klenerman, Mariolina Salio, and Vincenzo Cerundolo, and her research focused on presentation of bacterial antigens by MAIT cells. Below is a fantastic cake made for her by her lab colleagues.

Well done Dr Kulicke!

Congratulations to IITM student Tamara Davenne on passing her DPhil viva last Friday!

dav

Tamara undertook her research in the lab of Professor Jan Rehwinkel in the Weatherall Institute of Molecular Medicine. She investigated the metabolic role of the enzyme SAMHD1, how it regulates dNTP pools in cancer, and how this could lead to treatments for immunodeficiencies.

Well done Tamara, and good luck in your future career!

by Hannah Sharpe

The first year of the IITM DPhil consists of three rotations in different labs, covering a broad range of disciplines and research. To summarise the outcomes of the first rotation, the students gave poster presentations to their peers and supervisors. Here is an outline of the achievements of each project.

Robert Donat

Robert’s first rotation was in Simon Draper’s lab at the Jenner Institute, and contributed towards the development of a blood-stage vaccine for Plasmodium falciparum malaria infection. PfCyRPA forms part of a triple complex of proteins involved in Plasmodium merozoite erythrocyte invasion. Robert designed and made mutants of PfCyRPA through altering amino acids on the surface of PfCyRPA, and through addition of glycosylation sites. These mutants were tested in a growth inhibition assay using monoclonal and polyclonal anti-PfCyRPA antibodies.

Mari Johnson

Mari’s project was also related to malaria, and was conducted Dr Matt Higgins’ lab in the Biochemistry department. During her project, she investigated the widely-conserved HAP2 fusion protein involved in gametocyte fusion of Plasmodium, and how it could be used as a potential vaccine against malaria. During this project, Mari used Phyre and Pross modelling programmes to design structurally homologous proteins to HAP2, consisting of fused HAP2 alpha helical bundles and fusion loops, as well as whole HAP2 protein vaccines. These proteins were cloned into E. coli, and some of these protein constructs were successfully purified.

Lea Nussbaum

Lea worked in the lab of William James at the Dunn School. Here, she studied multinucleated fusion cells that arise during HIV-1 infection through the interaction of membrane-bound HIV-1 envelope proteins with CD4 and co-receptor molecules, and which can act as HIV-1 reservoirs in the brain. Lea showed that multinucleated macrophage-T cell fusion cells have similar gene expression pattern to macrophages but increased SAMHD1 phosphorylation. This was ascertained through development of a CEM T cell line expressing the HIV-1 Bal envelope protein, exposing them to macrophages, and using RNA expression analysis to measure gene expression.

Hannah Sharpe

Hannah’s first rotation project was with Professor Ellie Barnes, and aimed to characterise the T cell responses to rodent hepacivirus in infected and vaccinated rodents. Hannah used ELISpot assays to map the T cell epitopes in rats infected with RHV, and rats and mice vaccinated against RHV using a chimpanzee adenovirus-vectored vaccine. She then conducted intracellular cytokine staining to ascertain whether the epitopes elicited a CD4+ or CD8+ T cell response. The ultimate aim is to use RHV to develop an animal model of closely-related hepatitis C virus infection, in order to improve vaccine development and further research into HCV.

Sarah Wideman

Sarah’s first rotation project took her to Hal Drakesmith’s lab at the Weatherall Institute of Molecular Medicine. The Drakesmith lab researches iron deficiency, and how it can affect vaccine efficacy. Here, Sarah investigated how iron deficiency in murine T cells and dendritic cells have impaired proliferation, DNA synthesis, and cytokine production. She demonstrated that iron deficiency alters differentiation of antigen specific CD8+ T cells, and impairs antigen-specific T cell metabolism by using a Seahorse XF analyser to measure glycolysis, and that it also reduces dendritic cell cytokine production through flow cytometry and ELISA assays.

Overall, the first rotations were a success, and the first years are currently enjoying the first few weeks of their second rotation!

Layal Liverpool summarises the findings of a recent study she was involved in during her rotation and the first year of her DPhil in Jan Rehwinkel‘s lab. This article was first posted on the WIMM blog.

Viruses are basically packets of nucleic acid, DNA or it’s sister molecule RNA. Our cells have therefore evolved to recognise these molecules as a sign of virus infection. A recent study from Jan Rehwinkel’s lab in the MRC WIMM has revealed a new way in which cells sense and respond to invading viruses.

Infection is one of the biggest threats faced by our cells. To combat this, cells have evolved a highly-tuned detection system that relies on proteins called sensors. Viruses rely on nucleic acids, DNA or RNA, to infect cells and propagate themselves. Nucleic acid sensors in our cells exploit this by recognising DNA or RNA from invading viruses and activating potent anti-viral responses.

These early anti-viral responses are the cell’s first line of defence against an invading virus. One such response is a form of cell suicide called necroptosis. One of the nucleic acid sensors, called ZBP1 or DAI, can activate this form of cell death upon detecting herpes virus infection. By committing suicide, the infected cell sacrifices itself to stop the spread of the virus to other cells in the body.

Necroptosis is a “messy” form of cell death because it essentially involves the explosion of the cell, releasing all its contents into its surroundings. Here they can be picked up by patrolling immune cells, alerting them to the fact that there is a virus around.

Although ZBP1 was already known to activate cell suicide, exactly what from the virus ZBP1 was detecting had been a mystery. In their study, Jonathan Maelfait and colleagues in Jan Rehwinkel’s lab demonstrate that ZBP1 recognises RNA from the invading virus.

Like viruses, our cells also contain their own nucleic acids, for example the DNA that makes up our genes. A big question then is how nucleic acid sensors, like ZBP1, can tell the difference between the cells own nucleic acids and those coming from invading viruses.

Well, it might all come down to shape. In addition to the classical DNA double helix structure on the cover of every GCSE biology textbook, DNA – and RNA – can adopt another, more jagged, zig-zag shape named ‘Z’. In fact, ZBP1 is so-called because of its special ability to recognise Z-shape nucleic acids.

Maelfait and colleagues found that when they made cells with a broken version of ZBP1, which could no longer recognise Z-nucleic acids, the cells lost the ability to activate cell suicide in response to virus infection. Mice that have the same broken version of ZBP1 are more vulnerable to virus infection, probably because the lack of cell suicide allows the virus to persist and spread through the body more easily. This discovery suggests that the Z-shape might be an important molecular sign of virus infection, allowing cells to distinguish their own nucleic acids from those of viruses.

Understanding exactly how our cells make this distinction is important because when it goes wrong, it can lead to auto-immune or auto-inflammatory diseases. Clearly it would not be useful for our cells to start committing suicide when there is no virus! In the future, further investigation of nucleic acid sensing may reveal novel therapeutic targets for the treatment of viral infections and auto-inflammatory diseases.

References:
J. Maelfait, L. Liverpool, A. Bridgeman, K. B. Ragan, J. W. Upton, and J. Rehwinkel, “Sensing of viral and endogenous RNA by ZBP1/DAI induces necroptosis,” EMBO J, Jul. 2017.

Author: Layal Liverpool

If you would like to write a piece for the IITM blog please get in touch by emailing iitm@path.ox.ac.uk

Tamara Davenne shares her experience of presenting her research at an international conference.  

Last month I attended my first international conference. The Keystone symposium on type I interferon was held in Banff, Canada from the 19^th to the 23^rd of March. My abstract was accepted and I had the chance to present my work in the form of a poster, which was entitled: “SAMHD1 protects cells against apoptosis induced by dNTP overload”. This was a great opportunity to present and discuss my research. So my supervisor, Jan Rehwinkel, myself and another PhD student in our lab, Gregorio Dias, headed off to Canada!

Tamara (right) pictured with fellow PhD student and lab-mate Gregorio (left) in Banff, Canada where the conference was held.

Two main conferences were held at the same place at the Fairmont conference center: “Type I interferon (friend or foe?)” and “Pattern recognition receptors”. It was hard to decide which talks to go to, since they all sounded very interesting. Both main meeting rooms were next to each other which allowed people to easily leave in between talks to change rooms. Experts from all over the world were present and it allowed me to put faces to names and learn more about their areas of expertise.

The first challenge for me was remembering their names, their research focuses and a summary of their presentations/unpublished data. Focusing on talks for 8 hours a day during 4 days was intense, but extremely interesting! The second challenge was to network with fellow scientists. I am not particularly good at this so I wanted to improve, and the conference was a great place for that! I sat with new people almost every day at breakfast and dinner and it became very easy and natural after a few days – I really enjoyed it!

“I felt like a sponge: absorbing all this knowledge”

I felt like a sponge: absorbing all this knowledge and constantly thinking of how I could apply this to my specific research project. Could this new information help me to interpret some of the observations I have made in my own research? I found it very inspiring to see how people develop new tools and use them to address their scientific questions. This is what science is all about: getting out of your comfort zone and sometimes developing a technique no one has ever used before.

The poster session was very intense! I was tired of talking at the end of it, and that’s exactly how it should be. It is such a great pleasure to explain my research to interested people, to discuss and to listen to comments and suggestions. It is a good way to sense the general interest of people in your particular topic and, in my case, it was very positive. If you can get people interested in your project and explain to them why your research is relevant then it is a job well done!

The final discussion of “Type I interferons: friend or foes?” was very interesting and I think the take-home message from all the talks we attended was that everything is dose, time and context dependent. In the future, I think that more work will be needed to determine why there are so many different type I IFNs and how they differ from one another, for example in affinity or kinetics.

“I returned to Oxford […] with my head full of knowledge, inspiration and ideas.”

I returned to Oxford feeling tired from these intense few days, but with my head full of knowledge, inspiration and ideas. Going to an international conference is definitely an experience I would recommend. It is a very good investment of your time as what you gain from it is invaluable: networking skills, improved general knowledge and the opportunity to present your work and obtain new insights into your own project.” I am looking forward to my next conference!

Author: Tamara Davenne

If you would like to write a piece for the IITM blog please get in touch by emailing iitm@path.ox.ac.uk

Benjamin Nilsson tells us about his recent first author paper, which provides new insight into how the flu virus copies itself.

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