Emerging Viruses’ thesis prizes 2024 awards

They answered our questions

What is your academic background? Why did you turn to research?

Quentin Durieux: I always dreamed of becoming a veterinary surgeon, but being a rather average student, I wasn’t able to get into a preparatory school, which was necessary to pass the entrance exam. As I love biology and chemistry, I decided to do a degree in Chemistry-Biology at Grenoble Alpes University. Continuing in the same vein, I didn’t get very good results and almost failed my second year. It was during the third year of this degree that I developed a passion for structural biology, and my grades suddenly improved, enabling me to enter the Master’s in Integrative Structural Biology. It was during this Master’s that I was able to do laboratory internships at the Structural Biology Institute in Grenoble, where I met some incredible people who passed on their passion to me and taught me countless things.

The next step seemed clear to me: to do a thesis at this institute, which I was lucky enough to be able to do.

Adrian Gervais: I’ve always had a particular attraction for biology, medicine and animals, which is why I initially decided to do a BCPST (Biology, Chemistry, Physics and Earth Sciences) preparatory class, with the vague idea of becoming a veterinary surgeon. But during these two years of preparatory classes, I became interested in bioengineering. I studied the different paths and specialities offered by the schools that were accessible via the competitive entrance exams and I chose to join AgroParisTech for its biotechnology course. It was only at the very end of my engineering training that I decided to pursue research, thanks to an end-of-studies internship focusing on the research and development of diabetes drugs. I found it fascinating to set up, optimise, analyse and evaluate biological models to characterise therapeutic formulations.

With the idea of deepening my knowledge and skills in this field, I wanted to pursue a PhD in immunology combining basic research and clinical applications in an international environment, working alongside people using cutting-edge techniques in the life sciences. The Human Genetics of Infectious Diseases Laboratory, whose Paris branch is housed at the Imagine Institute on the Necker Hospital campus in Paris, was exactly what I was looking for.

Nell Saunders: After a scientific baccalaureate, I went on to study physics and chemistry in a preparatory class. I then went on to the Ecole Polytechnique, where I specialised in Biology. I did a double degree with the Ecole Polytechnique Fédérale de Lausanne, where I obtained my master’s degree. After completing my master’s thesis in Olivier Schwartz’s laboratory at the Institut Pasteur, I went on to do a PhD.

I went into research because it’s a profession where you can answer questions, find solutions and learn for the rest of your life. I think it’s a unique opportunity to work in a profession where you can do what you love and which is constantly evolving. I chose virology because it’s a dynamic field, where research can lead to rapid improvements in the detection, medicine and treatment of infections that affect millions of people.

What is the subject of your thesis?

Quentin Durieux: During my thesis, I worked on Bunyaviruses. These close cousins of the flu, although little known to the general public, infect people all over the world. In the vast majority of cases, the infection goes unnoticed, but it can also trigger serious symptoms. This is the case for the three viruses I studied:

• Hantaan can cause haemorrhagic fevers with renal syndrome;
• Sin Nombre can cause pulmonary syndrome (both members of the Hantavirus family);
• and finally La Crosse can cause severe and often fatal encephalitis in children under the age of 16.

Of course, I did not work on whole viruses. I focused on a central viral protein called RNA-dependent RNA polymerase. This protein enables the virus, after infection of a human, animal or plant cell, to replicate the virus genome (i.e. to make copies of the viral RNA). This activity is called replication. It can also use this viral RNA to produce mRNA, which can then be used by the cell to produce viral proteins. This second activity is called transcription.

To study it, I was lucky enough to be able to use the electron microscopes at the IBS. These microscopes use electrons to obtain a large number of images of my protein of interest, even if it is smaller than a few nanometres (10-⁹ m). Using computers and advanced image processing, we can then obtain the protein’s 3-dimensional structure and try to understand how the different elements that make it up work during these replication and transcription activities.

Adrian Gervais: When I started my thesis, the laboratory had just demonstrated that certain serious cases of COVID-19 could be explained by genetic or immunological anomalies. More specifically, these defects prevent the normal functioning of the type I interferon pathway, the key molecules produced in the first few hours of a viral infection to trigger the immune response. In this context, my thesis focused on the study of autoantibodies that block the action of these type I interferons. I wanted to find out how often they are found in the general population, and whether they could also explain the severity of other viral infections.

Nell Saunders: My thesis focuses on the study of the entry and replication of HKU1 and SARS-CoV-2.

After starting out studying variants of concern in SARS-CoV-2, I began working on the role of TMPRSS2 in the entry of HKU1, a seasonal coronavirus. The many tools developed during the pandemic in our laboratory and also by our collaborators for the study of SARS-CoV-2 enabled us to make major discoveries about HKU1. While TMPRSS2 was expected to act as a protease that cleaves the HKU1 spicule, we discovered that TMPRSS2 acts as a receptor for this virus. My thesis therefore focuses on proving the role of TMPRSS2 as a receptor for HKU1 in different systems, independently of its enzymatic activity. In collaboration with Prof. Rey’s team, we are studying the structure of the complex and the role of different amino acids in this interaction. In collaboration with Dr Lafaye’s team, we are studying the effect of TMPRSS2 blocking nanobodies on HKU1 entry.

What do you consider to be the most significant result of your thesis work?

Quentin Durieux: During my thesis, I managed to obtain the entire structure of the Hantaan virus polymerase. This is the first structure ever observed for a hantavirus polymerase. I also obtained this structure in different states of replication, giving us an overview of how this protein functions throughout this activity.

The most striking result for me was the discovery of an inactive state of the Hantaan virus polymerase. We were able to observe that this protein, in the absence of viral RNA, adopts a conformation that is not compatible with replication or transcription activity. It is able to switch to an active state by binding viral RNA. This inactive/active transition requires a movement within the active site that has never been observed before.

This discovery, coupled with the other structures, provides new information and new possibilities in the development of an antiviral molecule to combat infections caused by hantaviruses. This is all the more important as there is currently no approved treatment or vaccine against bunyaviruses.

Adrian Gervais: The major result of my thesis work is the implication of type I anti-interferon autoantibodies in 40% of encephalitis due to West Nile virus (WNV), whereas they are absent in individuals with an asymptomatic form of the disease. We have shown that these autoantibodies are present in the bloodstream prior to infection (and not produced in response to infection), and that they neutralise the antiviral effect of interferon against WNV. Spectacularly, they increase the risk of developing a severe form of WNV encephalitis by up to 500 times compared with individuals who do not carry them. Finally, we found these auto-Acs in the cerebrospinal fluid of a large proportion of severely affected patients, strongly suggesting their involvement in the neurological damage caused by the virus. Clearly, these results have made WNV encephalitis the best understood human infectious disease, with 40% of severe forms now explained.

Nell Saunders: The identification of TMPRSS2 as the HKU1 receptor is the major result of my thesis. Knowing the HKU1 receptor will make it possible to culture the virus in the laboratory on immortalised lines, whereas previously this was only possible on differentiated primary lines. This will significantly speed up research into this virus, and could prove useful in the event of the emergence of a new embecovirus.

What would you suggest to continue your work? What do you see as the major challenges in this field?

Quentin Durieux: The development of cryo-electron microscopy and the growing awareness of the danger of these viruses, which tend to spread over the last few years, have led to a number of discoveries about Bunyaviruses. The viral proteins that make them up are now a little better understood. However, research to date has generally focused on a single protein. Yet within a cell, these proteins interact and probably also with proteins in the cell, which they use to hijack the functioning of these cells to the advantage of the virus.

It will therefore be necessary to try and understand how these viruses ‘work’ within our cells. Where do they reproduce in the cell? What cellular proteins could be used by the virus? These are questions that will require in-depth, complex research and cutting-edge equipment.

Adrian Gervais: In addition to WNV encephalitis, I was involved in implicating type I anti-interferon autoantibodies in several other severe viral and arboviral infections. It seems, therefore, that we are currently unaware of the extent of severe viral infections that can be attributed to these auto-Acs. For this reason, it is vital to look for type I anti-interferon autoantibodies in any patient with a severe viral infection, on an agnostic basis.

Awareness of the importance of these autoantibodies in viral pathologies is a real medical challenge that could revolutionise the identification of patients at risk and improve their management. With this in mind, we have developed a simple, rapid diagnostic test capable of identifying defects in response to type I interferon, for use in hospitals.

From a scientific point of view, it is also essential to study the risk factors that lead to the production of these autoantibodies (including age), and the cellular and molecular mechanisms that allow them to appear – this is one of the laboratory’s major projects.

Nell Saunders: In order to continue the work, immortalised lines susceptible to HKU1 are being developed. These will enable us to study not only the entry of the virus but also other stages in its replication and exit. Studies will also help to understand the role of certain proteins, such as hemaglutinin esterase, in virus entry and release.

There are still many unanswered questions, particularly concerning the origin and evolution of HKU1. Increased sampling of different species may make it possible to identify related viruses in other species.

The use of anti-TMPRSS2 nanobodies in the clinic to treat respiratory infections caused by viruses cleaved by TMPRSS2 is also a way forward.

What are your career plans after your thesis?

Quentin Durieux: After my thesis, I started a post-doctorate at the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany. I moved away from the world of viruses to that of archaea and the nucleosome (protein interacting with DNA). I have, however, made sure that I stay close to cryo-electron microscopy, an incredible technique that is developing rapidly and enabling us to observe the world of the nanometre.

I hope one day to be able to return to France and obtain a permanent post that will allow me to continue studying viruses and, why not, Bunyaviruses.

Adrian Gervais: Since finishing my thesis, I’ve been working on a number of ongoing projects in the laboratory as a post-doctoral researcher, all related to type I interferon-mediated antiviral immunity. I then plan to do another longer post-doc in the pharmaceutical industry, particularly in the field of therapeutic innovations in immuno-oncology or viral infections.

Nell Saunders: I’m going to continue with a post-doctorate in Europe. Then my aim is to return to France to continue my research.