Current PhD projects based in Leiden

Student:  Vera van Vliet

Supervisors: Dr. ir. Marjolein Kikkert (Leiden) and Dr. Christine Tait-Burkard (Edinburgh)

Project:  Nidoviruses constitute the lethal human disease-causing SARS-CoV and MERS-CoV, as well as many highly important veterinary viruses such as avian infectious bronchitis virus (IBV).  For the human coronaviruses there are still no specific antiviral or prophylactic therapies available, and the available vaccines against IBV do not confer satisfactory protection against the devastating disease in chickens.

To tackle these problems innovations are desperately needed and we will focus on a combination of new approaches based on common viral protease activities exploited by all  these human and animal-infecting viruses during infection. These viral proteases commonly target specific cellular proteins for their own benefit, however, we have shown that extremely high-affinity sequence variants of these cellular ligands can work as very specific antiviral molecules. These protein-based antivirals could be expressed through genetic modification in the context of veterinary diseases or through protein delivery techniques in humans.

This project seeks proof of principle for the use of these innovative antiviral molecules in both human and animal-infecting nidovirus infections, including studies of viral resistance development.  We are using a series of infection models ranging from cell culture to primary cell models. Furthermore, a myriad of different techniques will be needed to develop the project, which will be learned and used in the first three years in Leiden. After this, the PhD student will have the opportunity to explore the possibilities for genetic modification and protein delivery in veterinary species in Edinburgh using the optimized antiviral ligands.”

Publications: "Ubiquitin variants potently inhibit SARS-CoV-2 PLpro and viral replication via a novel site distal to the protease active site"; Van Vliet et al 2022, PLoS Pathogens

Furthermore, I have presented at the Dutch Annual Virology Symposium, the “Viruses 2022 – At the Leading Edge of Virology Research” conference and had a Flash talk and poster at ASV2023.  To help support my time in Edinburgh, I have secured a FEMS Research & Training Grant, and a Leiden University Fund “Study trip” grant.

Student: Britt Nibbering

Supervisors:  Dr Romy Zwittink (Leiden, 3 years) and Prof Tanja Opriessnig (Edinburgh, 1 year)

Project:  Clostridioides difficile is the main causative organism of nosocomial diarrhea and develops in a disturbed gut microbiota as a result of previous antibiotic use. So called ‘hypervirulent’ strains, like C. difficile PCR ribotypes 027 and 078, are emerging, of which ribotype 078 is also increasingly recognized to cause infection in piglets. In the Netherlands, C. difficile PCR ribotype 078 is the second most frequently found type to cause community-acquired diarrhea.

The limited number of available effective antibiotics, in combination with increasing antibiotic resistance and virulence, urges new prevention and treatment strategies. As such, we need a better understanding of host and microbial factors that influence pathogenesis of C. difficile infection. In this project, host and microbial factors affecting colonization and infection by zoonotic C. difficile in humans and piglets will be studied.

To achieve this, two in vivo model systems will be applied; a controlled human infection model and an experimental piglet infection model. As such, host factors like the gut microbiome and immunological/metabolic parameters during colonization and infection will be characterized, as well as the genetic evolution of C. difficile during gut passage.

Student:  Maaike Swets

Supervisors:  Dr Geert Groeneveld (Leiden) and Prof Kenny Baillie (Edinburgh)

Project:  Viral respiratory infections have been a threat to public health throughout recent human history, and cause significant morbidity and mortality every year. Their ability to rapidly spread through populations and cause illness has led to continuous efforts to increase our understanding of viral disease. The last few decades have seen a massive increase in the use of different data sources for research in the field of viral respiratory diseases.

The increase of easily accessible, granular data from large populations allows for quicker understanding of infectious diseases. New pandemics of viral respiratory diseases are inevitable, and a serious challenge regarding new outbreaks is to coordinate research efforts and optimally use time and resources available.

In this thesis, we will use different data sources to increase our knowledge in the field of infectious disease surveillance and clinical practice, and improve the efficiency of research.

Publications from study:

1. Swets MC, Kerr S, Scott-Brown J, Brown AB, Gupta R, Millar JE, et al. Evaluation of pragmatic oxygenation measurement as a proxy for Covid-19 severity. Accepted for publication in Nature Communications, October 2023
2. Swets MC, Moss RJ, Kor F, Hilarius D, Moes DJA, Berkhout WE, et al. A comparison of the effectiveness of different doses of tocilizumab and sarilumab in the treatment of severe COVID-19: a natural experiment due to drug shortages. Int J Infect Dis. 2023 Feb;S1201971223000413.
3. Swets MC, Termorshuizen F, de Keizer NF, van Paassen J, Palmen M, Visser LG, et al. Influenza season and outcome after elective cardiac surgery: an observational cohort study. Ann Thorac Surg. 2023 Feb;S0003497523001443.
4. Turtle L, Thorpe M, Drake TM, Swets MC, Palmieri C, Russell CD, et al. Outcome of COVID-19 in hospitalised immunocompromised patients: An analysis of the WHO ISARIC CCP-UK prospective cohort study. PLOS Med. 2023 Jan 31;20(1):e1004086.
5. Swets MC, de Boer MGJ, Groeneveld GH. Nirmatrelvir Use during the Omicron Surge. N Engl J Med. 2022 Dec 29;387(26):2479.
6. Swets MC, Russell CD, Harrison EM, Docherty AB, Lone N, Girvan M, et al. SARS-CoV-2 co-infection with influenza viruses, respiratory syncytial virus, or adenoviruses. The Lancet. 2022 Apr;399(10334):1463–4.
7. Parkinson N, Rodgers N, Head Fourman M, Wang B, Zechner M, Swets MC, et al. Dynamic data-driven meta-analysis for prioritisation of host genes implicated in COVID-19. Sci Rep. 2020 Dec 18;10(1):22303.

Presentations:

• Poster presentation ID week 2022 (title: Mortality in influenza virus and SARS-CoV-2 co-infected patients treated with and without corticosteroids: an observational study)
• Poster presentation ECCMID 2023 (title: A comparison of the effectiveness of different doses of tocilizumab and sarilumab in the treatment of severe COVID-19: a natural experiment due to drug shortages)

Student:  Amy Barclay (née de Waal)

Supervisors: Prof Tom Ottenhoff and Dr Simone Joosten (Leiden) and Prof Anura Rambukkana and Prof David Dockrell (Edinburgh)

Project:  Tuberculosis (TB) kills 1.3 million people annually1, while Mycobacterium tuberculosis (Mtb) latently infects 25% of the world’s population2. Veterinary TB is a huge problem, calling for ONE-Health solutions in combatting TB. New experimental models for lung infection are crucial to increase our understanding of host-pathogen interactions, which is an essential step towards new drug- and vaccine-development.

However, neither conventional cell culture models nor animal models recapitulate the complexity of host-pathogen interactions in TB, particularly the early events. In particular, macrophage (Mf) function in the airway critically depends on interactions determined by cellular networks involving epithelial cells, which cannot be adequately modelled by conventional tissue-culture models. 

To address this bottle-neck, we will investigate host-pathogen interactions in pulmonary infections in recently established and innovative 3D-organoid cultures, combining epithelial cells with selected immune cell-subsets to dissect early infection events, including epithelial cell-fate changes which might promote pathogenesis together with innate immune cells.  The PhD-candidate will work both in LUMC (main base) and UoE.  The expected outcome of the project is to obtain fundamental insights in the early stages of host-pathogen interactions in innovative immune reconstituted 3D-tissue organoid-based culture models.  Primarily, Mtb is being studied as pathogen but the model can be used to investigate early events in other bacterial and viral infections, e.g. S.pneumoniae.

Publications: 

• Amy de Waal, Pieter Hiemstra, Tom Ottenhoff, Simone Joosten and Anne van der Does (2022) Lung epithelial cells interact with immune cells and bacteria to shape the microenvironment in tuberculosis, Thorax 77(4): 408-416
• Amy Barlcay, Dennis Ninaber, Suzanne van Veen, Pieter Hiemstra, Tom Ottenhoff, Anne van der Does and Simone Joosten (2023) Airway epithelial cells mount an early response to mycobacterial infection, Front. Cell. Infect. Microbiol., 26 September 2023