Fighting AMR in Oxford and Paris

To start off, can you tell us a bit about your experience before joining the Institut Pasteur?

WB: I began my studies with a degree in Biology at Imperial College, followed by a Masters in Virology which included a 6-month research project at the Francis Crick Institute.  It was at the Crick that I first heard about the Institut Pasteur from my mentor in the lab who said it was an amazing place to work.  Whilst at the Crick, I worked on a project investigating the human antibody response to SARS-CoV-2 and the molecular biology of the viral receptor ACE2.  This was in August 2020 to February 2021followed by an additional six months in the lab, so the height of the pandemic.  The research led to a growing interest for me in different aspects of coronaviruses.  Towards the end of my Masters, whilst researching PhDs, I learnt about the Pasteur- Oxford PhD around antimicrobial resistance and I thought it sounded like a good next step for me.

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So, you got the position at Institut Pasteur, and what did you focus on there?

I started in October 2021 as a PhD student in the UVI unit of Professor Olivier Schwartz at Pasteur.  The unit focuses on different aspects of coronaviruses such as the immune response and viral replication.  I was looking specifically at the replication and fusion of SARS-COV-2, which fed in well to the base of knowledge I had already acquired at Imperial and the Crick and had the bonus of being in Paris, making it a really different experience to what I would have gone on to do in the UK!  The UVI unit also studies other coronaviruses, including HKU1, which is actually what brought me to Oxford.

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It sounds like the perfect next step for you!  It would be great to hear a little more detail about the research you conducted once you were in the lab at Pasteur?

Sure, the overarching theme of my work at Pasteur is understanding more about the replication of the virus and the immune response. Specifically, I have been researching the role of cell-to-cell fusion during infection of the virus, producing multinucleated cells (also known as syncytia) and how these play a role in replication and disease. Additionally, I have worked on projects on the ways that antibodies interact with the virus to stop its spread. Within our lab at Pasteur, we are also interested in other human coronaviruses such as HKU1 which infect people seasonally and are partly responsible for the common cold and more severe diseases. Here, we are interested in how this virus replicates which led me to look at the main protease (Mpro) 3CL/ NSP5.  The (Mpro) 3CL/NSP5 of SARS-CoV-2 is an attractive antiviral target for human developed inhibitors such as the anti-viral medication Nirmatrelvir, due to its essential role in processing the polyproteins translated from viral RNA.  The team of Prof. Christopher Schofield at the University of Oxford have conducted a lot of work into the molecular mechanism of SARS-CoV-2 Mpro inhibitors and therefore we proposed a project, with the expertise at Oxford, to study these interactions in HKU1.

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And how did this translate to what you were doing at Oxford?

The project at Oxford was focusing on the activity and inhibition of the Mpro of HKU1, a Betacoronavirus, and one of four seasonal human coronaviruses, together with OC43, 229E, and NL63.  Together, these four viruses are responsible for 1.17 infections per year per child.  These are the milder of the seven coronaviruses known for their ability to infect humans, with the remaining three (SARS-CoV-1, Mers-CoV and SARS-CoV-2, the virus responsible for COVID-19) being more pathogenic and thus potentially more dangerous. 

The same Mpro protein in the SARS-COV-2 coronavirus has been extensively studied in the Schofield lab so this experience at Oxford provided a great opportunity to apply my research from Institut Pasteur in a biochemistry setting to look more deeply into the precise replication machinery of the viruses we study at Pasteur.

Unlike SARS-CoV-2, attempts at culturing HKU1in cell lines have been unsuccessful, meaning the viruses must be cultured in primary airway epithelial cultures which are expensive and difficult to manipulate.  Therefore, questions remain regarding the replication of HKU1. 

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And what kind of progress have you made so far?

We have recently isolated the HKU1 virus and so the next step is to investigate how HKU1 Mpro impacts the proteome of transfected or infected cells.  We do this using tools within the lab as well as assistance from the proteomic hub to further understand the replication of the virus.  The structure of HKU1 Mpro has been published. However, the sensitivity of HKU1 Mpro to inhibitors, and its specificity for cellular substrates are both currently unknown. Additionally, its stability and activity compared to SARS-CoV-2 Mpro are also unknown, so this was a large focus of my work in the Schofield laboratory at Oxford University.  Now I am back at Institut Pasteur, we have the tools available to study the efficiency of the inhibitors on HKU1 replication in primary cells to see how they impact on the virus as a whole. 

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It’s great to hear how well it all links up.  Would you say having done this joint programme enhanced your PhD experience both scientifically and professionally?

Absolutely - understanding how microorganisms interact with both ourselves, and the therapeutics we use to combat them requires research in different fields, to study this interaction from a cellular level to a molecular level. By combining the biological expertise at Institut Pasteur and the biochemical expertise at Oxford University, it has allowed me to study viruses from these different perspectives and has given me experience that I can take forward in my career.

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Viruses will always be a threat and the need for research and development into AMR and antivirals will always be important.  This joint PhD has provided me an invaluable angle, by allowing me to look at the virus at different levels. 

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And final question, you finish your PhD this summer- what is next?

After finishing at Pasteur, I hope to do a postdoc to continue virology research in academia. I am interested in viruses that impact humans but also ones that impact animals, particularly in agriculture, so it would be great to use my experience from the PhD in a slightly different field. Maybe a week or two of holiday as well after the defence!