In the frame of a Swiss National Science Foundation project, the Institute of Virology and Immunology (IVI), more precisely the group of the immunologist PD Dr. Marco Alves, interrogated the pulmonary responses to respiratory syncytial virus (RSV) infection in early life. This work provides novel insights into the host’s contributing factors of RSV disease severity and points to an inappropriate immune response of the immature lung. Furthermore, we identified mesenchymal stem and stromal cells as key elements in repair and regeneration of the lung following RSV-mediated injury. “The PhD thesis work of Melanie Brügger provides new insights into the mechanisms of RSV pathogenesis during the critical period of early life and may have therapeutic implications”, says PD Dr. Marco Alves thesis supervisor of Melanie Brügger.
Exploring repair and regeneration after respiratory syncytial virus (RSV)-mediated acute lung injury
Interview with Dr. Melanie Brügger about her PhD thesis on the subject of RSV
What was the goal of your PhD?
The goal of my PhD project was to investigate the role of a particular cell type of the lung during RSV disease, namely mesenchymal stem and stromal cells (MSCs). MSCs have been shown to be crucial during lung development, regeneration, and the maintenance of homeostasis. However, only very little is known about these cells in the context of respiratory virus infections and subsequent lung injury. The project started with the beginning of my PhD, which means I started almost from scratch, establishing several methods and exploring different hypotheses.
What are your findings?
I identified a novel function of lung MSCs during RSV-mediated acute lung injury. In fact, this cell type is involved in distinct steps of host response to RSV infection. Specifically, I could show that MSCs can mount an antiviral response following infection, which might contribute to viral clearance and resolution of the disease. Furthermore, severe RSV infection leads to lung injury with detrimental long-term consequences. My findings suggest that MSCs are involved in the repair and regeneration of RSV-mediated lung injury. We assume that this is also relevant for other severe respiratory virus infections. Interestingly, I also found that MSCs can be targeted by RSV in vivo.
What does it mean for the future, why is this relevant and for whom?
With this study we contribute to the understanding of host response following RSV infection and lung repair mechanisms during the highly critical period of early life. We showed that MSCs are involved in RSV disease and following injury, MSCs seem to be beneficial for the regeneration and repair processes. Therefore, the active role of MSCs during RSV infection may have therapeutic implications during severe disease. In fact, due to their characteristics, MSCs are intensively studied for cell-based therapy approaches to reduce acute lung injury, e.g. also in the course of the ongoing COVID-19 pandemic.
What are you most proud of in your work?
Most of my experiments were based on primary cells and different culture systems, which mimic the lung. However, certain complex questions, concerning the disease or repair and regeneration mechanisms, could not be answered with cell culture systems. Therefore, we applied the lamb model of RSV infection, which mimics very well the human and bovine disease. The work with animal models is highly complex, challenging and requires a high degree of dedication. During three subsequent years, our group together with different collaborators performed investigations, each lasting for several weeks or even months. Thereby I could surpass myself and I'm proud that I significantly contributed to the successful accomplishment and even more that I was highly involved in the planning and coordination of the studies. Also, I'm very happy that during my PhD I could always continue to play “Korbball” in the NLA. This was an important balance and also helped me to stay persistent and patient in the lab.
What did you like most during the PhD ? What do you like working in research in general?
One of the things I like most about research is the variation in the job, which includes hands-on experiments, subsequent analysis and interpretation of the results, but also presentation of the data at meetings and congresses. During my PhD, I had the chance to work with a variety of models such as primary cell cultures, 2D and 3D airway cultures, as well as an in vivo model. Another thing I highly appreciate is the interaction with other people in the lab and the exchange and discussions of findings and ideas. I also had the opportunity to co-supervise a Master’s student and I enjoyed to teach and to see him develop in the lab.
How was your time at the IVI? What did you like most?
At the IVI, I had the chance to interact with many different people with diverse backgrounds. Thereby I could profit a lot, learn a huge variety of techniques, and meet many great persons. Furthermore, thanks to the special infrastructure and the huge knowledge and experience at the IVI, I had the unique opportunity to work with the lamb model of RSV infection. To my knowledge, there is only one other lab, located in the USA, which has the possibility to work with this model. Although very intense and emotionally challenging, it was a unique experience to investigate RSV infection using a physiological model. For everybody in the team it was very clear to work extra carefully and to take the most possible out of it. We hope that with the resulted two publications (Démoulins et al. PLOS Pathogens 2021 and Brügger et al. PLOS Pathogens 2021) we can contribute to the understanding of severe RSV infections and eventually help in progressing in vaccine design or other treatments.
What are your next steps?
After successfully defending my thesis, I decided to continue as a post-doc in the group of PD Dr. Marco Alves, working on a new project on the subject of SARS-CoV-2. While my main focus will be on this project, I would also like to take the advantage to explore some questions left open during my PhD. Also, I would like to extend my network in the field, promote collaborations, and start to write grant applications, since after this stage I'm looking for a new challenge, probably somewhere abroad, but certainly in research.
Mesenchymal: Refers to cells that develop into connective tissue, blood vessels, and lymphatic tissue.
Lung homeostasis: Quiescent state of the lung. While tolerance to harmless inhaled particles is ensured, efficient and rapid immune responses can be mounted against invading pathogens.
The respiratory syncytial virus (RSV) is a major cause of severe lung infections in infants and young calves. In human, RSV is a seasonal virus with increasing numbers during the winter months. However, due to the COVID-19 pandemic associated measures, there were almost no RSV cases in the winter season 2020/21. Alarmingly, several countries across the world, including Switzerland, reported an increase of RSV infections this summer. In calves, RSV is a major cause of severe respiratory infections leading to bronchopneumonia.
To date there is no licensed vaccine available in human and the vaccine used to protect young ruminants shows low efficacy. This emphasizes the importance of studying this virus and its disease.
Last modification 13.09.2021