Projects available based in Leiden

Description of PhD projects Integrated One Health Solutions that will be based at Leiden University Medical Centre. Start date for projects is flexible.

Cellular protein variants as potent and versatile antiviral agents against human and veterinary corona- and arteriviruses

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

Contact: Dr. ir. Marjolein Kikkert

Nidoviruses constitute the lethal human disease-causing SARS-CoV and MERS-CoV, as well as many highly important veterinary viruses such as porcine reproductive and respiratory syndrome arterivirus (PRRSV).  For the human coronaviruses there are still no specific antiviral or prophylactic therapies available, and the available vaccines against PRRSV do not confer satisfactory protection against the devastating disease in pigs.

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 will seek 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 will use a series of infection models ranging from cell culture to ex vivo (lung) models, and mouse 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.

Zoonotic Clostridioides difficile colonization and infection

Supervisors:  Dr Romy Zwittink (Leiden) and Prof Tanja Opriessnig (Edinburgh)

Contact:  Dr Romy Zwittink

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. 

The PhD candidate will become part of a dynamic team of infectious disease and microbiome experts from the Leiden University Medical Center (LUMC), the University of Edinburgh (UoE) and the Iowa State University (ISU). LUMC hosts the National Reference Laboratory for C. difficile infections, the Center for Microbiome Analyses and Therapeutics and the Controlled Human Infection Center. UoE and ISU provide expertise in piglet model development and application. The diverse nature of this project, encompassing in vivo trials, hands-on laboratory work and computational analysis of big data, provides a wide-range of knowledge/skill development opportunities for the PhD candidate.

Asymptomatic Influenza virus infection is a risk factor for ARDS after surgery

Supervisors:  Dr Geert Groeneveld (Leiden) and Dr Kenny Baillee (Edinburgh)

Contact:  Prof Geert Groenveld

Project:  Acute respiratory distress syndrome (ARDS) is an acute inflammatory response in the lungs leading to respiratory distress and is considered a life-threatening complication after cardiac surgery. A number of concurrent risk factors are associated with development of ARDS. Asymptomatic respiratory viral infection — for example, influenza — could prime the lungs and could therefore be an avoidable risk factor for ARDS after cardiac surgery. 

Within a dedicated research team, you will do a multicentre study in patients undergoing elective cardiac surgery to determine causal relation between asymptomatic viral infection (Influenza or any respiratory viral agent) and ARDS. In addition, preventive effect of influenza vaccination will be assessed. In order to explore pathogenetic mechanisms underlying susceptibility to ARDS, whole blood RNA samples from a subset of samples will be sequenced using CAGE (cap analysis of gene expression) to detect influenza-specific patterns of gene expression. In addition, a pig model might be used to assess genetics of the host-pathogen interaction. 

During this PhD program, you will learn the best from both Edinburgh and Leiden research programs and you will be trained in conducting highly relevant research on the interface between clinical studies and basic science.

Empowering antibiotics using host defence peptides to fight antimicrobial resistance in respiratory infections 

Supervisors:  Dr Peter Nibbering and Prof Pieter Hiemstra (Leiden) and Prof Donald Davidson and Dr Marc Vendrell (Edinburgh)

Contact:  Dr Peter Nibbering

Project:  Antimicrobial Host Defence Peptides (HDP) show great promise in combating multidrug-resistant (MDR) bacteria.  We have developed a new class of synthetic antibacterial and anti-biofilm peptides (SAAPs), with enhanced activity against MDR pathogens.

We will screen libraries of SAAPs and analogues developed in Leiden, modified variants (e.g. PEGylated), and novel peptide sets (based on endogenous humans, chicken and pig HDP) for their ability to enhance i) host defences, and ii) efficacy of conventional antibiotics against MDR bacteria, i.e. MRSA, Pseudomonas aeruginosa and Streptococcus pneumonia (including those within biofilms).

Antimicrobial activity of selected peptides will be verified in presence/absence of antibiotics on the apical surface of air-liquid cultured airway epithelial cells. In addition, candidate peptides will be screened for complementary protective innate immune-enhancing impact on neutrophil and macrophage function( e.g. ROS production, chemotaxis, phagocytosis and bacterial killing). The antimicrobial properties of of these HDP and antibiotics will also be studied in epithelial cell cultures pre-exposed to inducers of endogenous HDP.

Finally, optimal synergistic HDP and antibiotic combinations will be evaluated in in vivo infection models to identify novel therapeutic approaches to combat MDR bacteria and enhance the innate immune system.

Dissecting respiratory bacterial infection biology, including tuberculosis, using a novel human lung organoid - immune cell co-culture model

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

Contact:  Dr Tom Ottenhoff

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 will be studied as pathogen but the model can be used to investigate early events in other bacterial and viral infections, e.g. S.pneumoniae. The PhD candidate will benefit from the strong combined interdisciplinary expertises from different research areas at both Leiden and Edinburgh. The complementary expertises of the research groups involved will provide the PhD candidate with unique opportunities to utilize these expertises and extend the research areas in the project. The proposed candidate will have the opportunity to become a super-specialized expert in modelling early interactions in airborne infectious diseases.

The project is highly innovative using cutting edge technologies to address interdisciplinary questions, and will provide unique opportunities for further personal scientific and career development of the candidate in science, particularly incorporating multiple disciplines to address research questions.

Projects available based in Edinburgh

Description of PhD projects in Integrated One Health Solutions that will be based at the University of Edinburgh. Students will start in September 2020.

Rapid identification of pathogens utilising MinION technology

Supervisors:  Dr Kate Templeton (Edinburgh) and Dr Eric Claas (Leiden)

Contact:  Dr Kate Templeton

Project:  Rapid identification of the etiologic agent of an infectious disease is essential for best management, setting up treatment and preventive measures. The current approach requires that specific pathogen identification is performed by direct diagnostic tests which normally include culture and PCR-based assays. Although these approaches are highly specific and well validated, they suffer a number of limitations. In addition many of the current techniques are relatively slow taking several days to deliver results  and often are biased to one or two pathogens and don’t capture the complexity of the full microbial picture.

Rapid identification of the etiologic agent of an infectious disease is essential for best management, setting up treatment and preventive measures. The current approach requires that specific pathogen identification is performed by direct diagnostic tests which normally include culture and PCR-based assays. Although these approaches are highly specific and well validated, they suffer a number of limitations. In addition many of the current techniques are relatively slow taking several days to deliver results  and often are biased to one or two pathogens and don’t capture the complexity of the full microbial picture. 

The aim of this PhD project is to develop a rapid, genome sequence-based, diagnostic approach to optimise management of infections, focussing on (i) Challenging cases; (ii) Rapid delivery at point of impact and (iii) Poly microbial diagnosis.

Exploiting Klebsiella pneumoniae genomics for One Health diagnostics

Supervisors:  Dr Thamarai Schneiders (Edinburgh) and Dr Els Wessels, Ed Kuiper and Eelco Franz (Leiden)

Contact:  Dr Thamarai Scheniders

Project:  Klebsiella pneumoniae (Kp) represents a major threat to human and animal health where this challenge has met significant efforts in genome analyses to elucidate the factors that contribute to its population structure, pathogenicity status and critically, its antimicrobial resistance.

Previous studies have demonstrated that the population structure of Kp encompasses specific traits that delineate human, animal and environmentally associated strains. Whilst these gene specifications are useful, there remains a critical need for greater discrimination of Kp genomic sequences for population-based analyses within complex datasets e.g. metagenomic data.  As such the overarching aim of this project is to expand our ability to probe complex metagenomic or microbiome datasets to dissect the prevalence, transmission potential and the emergence of Kp; not least in developing tools for rapid diagnostics.

The key aims of this project are to (i) establish greater discrimination of Kp population structure, (ii) Validation and Identification of specific markers, identified in Aim 1, in complex datasets. The outlined proposal will extend and produce novel insights into the population structure caused by the major nosocomial pathogen Klebsiella pneumoniae.

The project will undertake both bioinformatic and microbiological validation of datasets and Kp strain collections. This approach has significant implications in reviewing Kp carriage, transmission and current diagnostics from the human, animal and environmental perspective. Ultimately, this approach will result in a prediction model applicable in routine diagnostic microbiology for risk estimation for spread and development of infection.   The student will be entrenched in vibrant microbiology community within the University of Edinburgh, LUMC and RIVM.

The proposed project allows the student to build strong bioinformatic skills in probing Klebsiella population structure and applying these findings into complex datasets. Additionally, there are multiple opportunities to biologically validate these bioinformatic targets thus facilitating student training in both computational and biological approaches in studying Klebsiella pneumoniae.

Development of multibiomarker Point-Of-Care test for detection of bovine tuberculosis and assessment of vaccine efficacy

Supervisors: Prof Jayne Hope (Edinburgh) and Dr Annemieke Geluk (Leiden)

Contact:  Prof Jayne Hope

Project:  Mycobacterium tuberculosis, the causative agent of human tuberculosis (TB), causes more deaths than any other single human infectious disease worldwide.  In addition, M. bovis, causing TB in cattle, leads to significant economic losses to the agricultural sector, and represents a major zoonotic disease challenge. For both human and bovine TB there is an urgent need for sensitive and specific point-of-care (POC) diagnostic tests. Such tests will represent major game-changers, particularly in low resource settings. 

This PhD project aims to develop a low complexity, diagnostic test for bovine TB detection in the field based on a quantitative lateral-flow assay format suitable for multiplex detection of cytokines and antibodies at POC level. This test format, pioneered for human TB, will be translated for detection of bovine cytokines based on a 6-biomarker signature specific for active human TB.  Novel serum proteins will be assessed for their potential to detect disease, infection and vaccination and evaluated in the POC format using samples from cattle under experimental, and field conditions. The results established using the novel POC diagnostic test will be compared to the currently available diagnostic tests. 

This project builds on extensive and unique research expertise of the collaborating groups in human and bovine TB immunology and vaccinology as well as POC-test development. It will benefit from multiple, ongoing international collaborations and state-of-the-art research facilities and education programs at The Roslin Institute and Leiden University Medical Centre.

How does post-translational modification and intracellular localisation of antiviral IFITM proteins regulate their activity and their ability to act as barrier to zoonotic virus transmission?

Supervisors: Dr Richard Sloan (Edinburgh) and Dr Marjolein Kikkert (Leiden)

Contact:  Dr Richard Sloan

Project:  Interferon Induced Transmembrane Proteins (IFITMs) are host innate immune proteins that inhibit cell entry of a wide range of viruses of global importance including influenza A virus, HIV, dengue virus, Ebola virus, SARS-coronavirus (CoV), MERS-CoV, chikungunya virus and Zika virus[1]. The ability of IFITMs to inhibit viruses depends on their cellular localisation and post-translational modification. 

The aim of this project is to show how genetic variation in IFITM alleles from a panel of species results in variation in their post-translational modification and antiviral efficacy, thus exerting a barrier to cross species virus transmission. It will use range of molecular and cellular approaches to define this in the context of viral infection for a number of emerging viruses. The project will also include confocal imaging, flow cytometery working in a biocontainment safety level 3 (BSL3) lab, and live animal (mouse) infection work, the latter with a particular emphasis on coronavirus infection. The project entails 3 years research at Edinburgh University, and with the fourth and final year based in Leiden University in the Netherlands. 

Studentships will be awarded competitively and are open to candidates from any country in the world. All applicants should hold at least an upper second class degree or equivalent in a relevant discipline, e.g. immunology, microbiology, biochemistry, biology or fields related to the specific project.

Fixed-term contract: 4 years.

The successful applicants will be awarded a 4 year studentship, which includes their stipend and tuition fees, regardless of country of citizenship. Funding also covers contributions towards travel, up to 12 months living expenses at the second centre and research costs for their PhD project.

Leiden University Medical Center and University of Edinburgh

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