Infection, Immunology & Translational Medicine (IITM) Oxford

News and Blog

Sensing viruses: shape matters

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

 

Malaria Hotspots and How to Find Them

Richard Morter explains the findings of a recent study he was involved in during his rotation project at the KEMRI-Wellcome Trust Research Programme in Kenya.

Malaria is a mosquito-transmitted parasitic infection and although it is treatable if diagnosed early enough, approximately half a million people die each year from malaria. Around 70% of these deaths are in children under the age of five.

Malaria therefore presents a huge burden to global health. Although incidence is reducing globally, there is still a long way to go to reach elimination. The most effective tools currently used to control the spread of malaria are the insecticide-treated bed nets and indoor residual spraying (the application of insecticides to the walls of people’s homes where mosquitos might rest).

 

Picture1

Credit: UNICEF

 

Traditionally, malaria control programmes have involved blanket coverage of endemic areas, where every single house in an area is given bed nets or has their houses sprayed. However there is growing interest in adopting more targeted approaches where only those most at-risk are selected for intervention.

The advantage of this is largely economic. The hope would be that targeted intervention in a defined geographic area would yield the same overall reduction in malaria transmission as blanket coverage, but using fewer resources. This would mean more areas could be covered for the same cost leading to a more universal reduction in malaria transmission.

Malaria transmission intensity is inherently uneven across different areas. It’s unevenly spread across the tropical world with sub-Saharan Africa accounting for over 90% of all cases. It’s unevenly spread within Africa too. This unevenness is called spatial heterogeneity of transmission intensity.

 

Picture2

Credit: Malaria Atlas Project – University of Oxford

 

In fact; as we zoom in on smaller geographic areas, we continue to see spatial heterogeneity. We can even see it right down at the single homestead level – infected children are not uniformly spread across a village but instead are tightly clustered together, living in either the same or adjacent homesteads. These locations are described as ‘hotspots’ of malaria transmission and could be targeted for control interventions.

Hotspots have been identified by our group in nearby villages along the Kenyan coast, Junju, Ngerenya and Ganze. Junju has moderately high transmission intensity whereas Ngerenya and Ganze have very low transmission intensity.

For targeted interventions to work, hotspots need to be detected accurately. In this paper, we investigated just how accurate current methods are in detecting hotspots.

The first question to ask is; do hotspots remain stable over time? In other words, if we use a previous year’s hotspot data, and direct control interventions to those locations, will the hotspots be in the same place the next year or are we chasing a moving target? In this study, we discovered that the hotspots are indeed stable over time in the high-transmission village, however there appears to be less stability in the lower-transmission villages. What may be required in the future is a more real-time approach where hotspots are detected as they form and immediately targeted.

The second question we addressed is; what method should be used to detect hotspots? We used three different methods to detect parasite infection and subsequently identify hotspots; microscopy, rapid diagnostic testing (RDT) and qPCR.

The gold standard method for malaria diagnosis is microscopy. It’s cheap and already almost universally available in malaria endemic areas, however it lacks sensitivity meaning infections with low numbers of parasites are often not detected.

 

Picture3

Malaria-causing P. falciparum parasites in a thin blood film

 

RDTs work in a similar way to pregnancy tests and a band appears on the test stick if the blood sample contains parasites. They are also relatively cheap and might have slightly better sensitivity to microscopy.

A much newer and more sensitive tool is qPCR where parasite DNA in a blood sample is amplified in an enzymatic reaction. This amplification is detected and indicates a positive sample. qPCR can detect positive samples with much lower parasite counts than microscopy or RDTs, however it’s expensive and requires more specialist equipment.

We compared the abilities of microscopy, RDTs and qPCR to detect hotspots in settings of different transmission intensities and assessed the degree of overlap between hotspots detected by the methods. We found that hotspots were easily detected by all methods in the high transmission setting but microscopy was less reliable in the low transmission setting. The degree of overlap was least for RDTs. Microscopy also became more inconsistent and the hotspots it was detecting overlapped less with qPCR in the low transmission setting.

This is because RDTs and microscopy are less sensitive methods so are less reliable in being able to accurately detect hotspots especially when there are fewer positive samples. Because of this, we suggest that qPCR should preferentially be used particularly as transmission intensity decreases.

Overall, targeted malaria control programmes are an important part of elimination campaigns. Hotspots become more apparent as transmission intensity falls and becomes patchier, therefore hotspot targeting will become even more important in the future as global malaria incidence gradually declines. We found that qPCR becomes more important in this situation. More needs to be done to increase the accessibility of qPCR in malaria-endemic low and middle income countries by reducing cost and simplifying technologies.

Together, these strategies may help contribute to controlling and eventually eliminating malaria worldwide.

The full paper can be accessed at: https://doi.org/10.1093/infdis/jix321

Polycarp Mogeni, Thomas N. Williams, Irene Omedo, Domtila Kimani, Joyce M. Ngoi, Jedida Mwacharo, Richard Morter, Christopher Nyundo, Juliana Wambua, George Nyangweso, Melissa Kapulu, Gregory Fegan, Philip Bejon; Detecting Malaria Hotspots: a comparison between RDT, Microscopy and Polymerase Chain Reaction. J Infect Dis 2017 jix321. doi: 10.1093/infdis/jix321

Author: Richard Morter

Richard is now undertaking a collaborative DPhil project between the Jenner Institute, University of Oxford and the KEMRI-Wellcome Trust Research Programme, supervised by Professors Adrian Hill and Philip Bejon. He is characterising the Regulatory T cell response in a human malaria challenge model and looking at the consequences of malaria-induced Regulatory T cells on effective vaccination against malaria.

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

Hannah Behrens: Transforming my research into medicine

Every IITM student writes a review shortly after starting their PhD project. Often this is about the literature directly relevant to their thesis. In my case it was different; a very good recent review about the background to my thesis already existed. Instead I decided to have a look at how the toxins I study could be transformed into medicine.

 

Hannah review blog

 

Bacteriocins, the toxins I study, are not toxic to humans but instead very specifically kill certain species or strains of bacteria. The bacteriocin most of my work focuses on, for example, is produced by a bacterium called Pseudomonas aeruginosa to kill other strains of the same species; its cousins, if you wish. This way they can defend or conquer ecological niches. Can we exploit these bacteriocins as antibiotics to treat bacterial diseases in humans?

 

Searching for evidence

Last summer I set out to find all the reports of people who had tried these bacteriocins to cure infections in animals. I found eleven such reports and two additional ones which just looked at the effect of bacteriocins in healthy animals. Finding these reports was the most difficult part of all. Most reports I read turned out to be irrelevant. One I had to request from the libraries’ archives. It was so old it only existed on paper, as compared to most scientific reports which can now be found online. I went up to the top floor of the Bodleian library in Oxford where I received an old linen-bound book.

Of the eleven studies I found, only six, all from this century, had actually identified the exact bacteriocin they worked with. Previously researchers had realized they were working with something toxic but were not yet able to identify it.

Next I analysed the data I had found. It looked very promising. In all cases the bacteriocins were able to resolve or reduce bacterial infections – something that keeps me motivated on days when my research is not that easy!

 

Better than traditional antibiotics?

One question you might have asked yourself is, but why do we even need new antibiotics? Don’t we already have many? We have 26 but our frequent (over)use during the last century has led to many bacteria developing resistance. In the past few years more and more cases of bacteria resistant to all antibiotics occurred. Meanwhile the development of traditional antibiotics has stalled since the last major discovery of a new drug back in 1987. Scientists are now turning to an array of alternative antibiotics to plug the growing gap. One very promising type are narrow-spectrum antibiotics, such as bacteriocins.

Bacteriocins only kill one species of bacteria or even a subset of that species. This is in contrast to traditional antibiotics which kill a wide range of bacteria. I like to think about it like this: Something as different from you as a tree, causes a disease. Nonetheless you are wiped out with it because you happen to belong to the same kingdom of life as the tree. This is exactly how broad the spectrum of traditional antibiotics is. Bacteriocins however have such a narrow spectrum they can differentiate between you and your cousin (figuratively speaking).

The disadvantage following from that is that one needs to identify the species and maybe even strain of bacteria causing an infection before starting the treatment. The huge advantage is however that only those bacteria that cause the infection are treated. Because traditional antibiotics kill all types of bacteria they also select for resistant mutants in all types of bacteria. With narrow spectrum antibiotics only one species out of the millions we carry in our body is put under selective pressure. (Selective pressure kills most but encourages the spread of resistant survivors). This way, narrow spectrum antibiotics, such as bacteriocins, do not promote antibiotic resistance.

The broad killing spectrum of traditional antibiotics also means that the delicate balance of health-related “friendly” bacteria in our body gets disturbed. Especially in elderly and weak people this can have devastating, even lethal effects, such as promoting C. difficile infections. The beauty of narrow spectrum antibiotics is once again that they leave all bacteria that are not related to the infection unaffected.

These aspects and some others which will determine the success of bacteriocins as antibiotics I have discussed in the second part of my review article. Especially helpful for this part was my Co-author Dr. Anne Six from Glasgow. Together we polished the article until we decided it was ready to submit. After incorporating some advice from the reviewers our review has finally been published. You can now read it here.

Author: Hannah Behrens

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

References:

Behrens, H.M., Six, A., Walker, D. and Kleanthous, C. (2017) The therapeutic potential of bacteriocins as protein antibiotics. Emerging Topics in Life Sciences. 1(1) 65-74

Internship opportunities at DJS Antibodies

 DJS Antibodies are looking for summer interns. This is a great opportunity for anyone considering a move into business, pharmaceuticals, biotechnology or management consulting – or just interested in a career beyond academia! IITM alumnus Joe Illingworth is a founder and CEO at DJS antibodies. More information about the company and details of the two available positions are provided below.

DJS Antibodies is a biotechnology start-up funded by Oxford Sciences Innovation (OSI) and Johnson & Johnson Innovation. Our novel technology unlocks the potential for discovery of therapeutic monoclonal antibodies against previously undruggable disease targets. Antibody therapies are becoming extremely important for the treatment of many diseases with the global market for therapeutic antibodies approaching $100 billion. By combining our unique technology with new and exciting biology, DJS is striving to produce the next generation of novel therapeutics for the treatment of major modern healthcare challenges.

DJS ANTIBODIES – DATA SCIENCE/DATA ENGINEER INTERN

Contact: David Llewellyn (CEO) david.llewellyn@djsantibodies.com

Position

We are looking to recruit an intern capable of building programmes to search databases and identify druggable diseases with high unmet medical needs. The successful applicant will receive competitive remuneration.

The intern will work closely with the company’s Chief Scientific Officer and a medical sciences intern, to:

  • Develop algorithms to scan databases and rapidly triage academic and industry literature.
  • Identify associations between human biology, disease, clinical processes, and economic drivers of the pharmaceutical industry.
  • Prioritise disease areas for an R&D investment.

This is an excellent opportunity for a student with experience in programming, who is interested in a career in consulting, the pharmaceutical industry, or biotechnology. The successful applicant will gain an overview of the biopharma industry while working on a project which will meaningfully influence the R&D strategy of a dynamic biotech company.

Skills

Applicants should be junior/intermediate Python developers and be comfortable with using the Python ecosystem to:

  • Interface with external APIs.
  • Perform basic data cleaning and analysis.
  • Build presentations and export results to other formats (e.g. Excel).

It would be beneficial to have experience with pandas, requests, numpy, and matplotlib. Location: Remote work
Duration: 8-12 weeks over the summer period (flexible dates)

DJS ANTIBODIES – MEDICAL SCIENCES INTERN

Contact: David Llewellyn (CEO) david.llewellyn@djsantibodies.com

Position

We are looking to recruit a motivated person with a broad interest in disease biology and drug development. The successful applicant will receive competitive remuneration. The position will involve analysing academic and industry literature to identify high value druggable pathways.

The intern will work closely with the company’s Chief Scientific Officer and a programming specialist to:

  • Build and exploit basic software tools to extract relevant information from public databases.
  • Assess relationships between biological signalling pathways and disease.
  • Establish relationships with key opinion leaders in different disease areas.
  • Develop plans for the progression of new therapeutic monoclonal antibodies through pre-clinical testing.

This position represents an excellent opportunity for a student of medicine, biomedicine, biology, physiology or biochemistry looking for experience in working on key strategic projects within a small company, or considering a move into pharmaceuticals, biotechnology or management consulting.

Location: Remote work
Duration: 8-12 weeks over the summer period (flexible dates)

Tamara Davenne presents at Keystone Symposium in Canada

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 19th to the 23rd 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!

Keystone 2017b

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

Taking apart the flu virus copying machine

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

(more…)