Research Focus

Immunology & Infectious Diseases

Area of Research

Interactions between host and pathogen applying systems biology methods. Pathophysiology and transmission of viruses and bacteria. Improvement of existing diagnostics and development of novel diagnostic methods and prevention strategies

Cumulative research grants (PI, co-applicant or partner) since 2014: CHF 39.9 Mio.

(i) Personalized Swiss Sepsis Study (SPHN/PHRT-funded grant, CHF 5.3 Mio). Building a Swiss wide infrastructure for clinical data warehouses and development of digital and molecular biomarkers for early sepsis recognition using machine learning. Role: Principal investigator – study design, coordination, special focus whole genome sequencing of bacterial isolates. In collaboration with all Swiss University Hospitals and Universities (ID, ICU and microbiology divisions; see www.sphn.ch) and ETH Zurich groups. Active. 

(ii) Screening for multi-drug resistant pathogens: usage of rapid metagenomic technologies for screening and surveillance. (SNF funded grant, CHF 0.75 Mio). Developing a shotgun long-read metagenomic-based protocol for rapid screening and pathogen assessment in regard of antimicrobial resistance. Role: Principal investigator – study design,  c oordination, collection of samples and supervision of PhD student and Post-doctoral fellow (see http://p3.snf.ch). Active. 

(iii) Developing microbials to fight extended beta-lactamase (ESBL)-producing Escherichia coli (Gebert Rüf-funded project, Microbials, CHF 0.45 Mio). Exploring colonization and decolonization with ESBL-producing E. coli in order to identify potential microbials to outcompete drug-resistant E. coli. Role: Principal investigator – study design, coordination, whole genome sequencing of bacterial isolates, data analysis. In collaboration with ETH Zürich groups (W.D. Hardt, S. Bonhoeffer) and Swiss Tropical and Public Health group (E. Künzli) (see https://www.grstiftung.ch/de/media/portfolio~grs-060-18~.html). Active.

(iv) Swiss Pathogen Surveillance Platform (NRP72-funded project, CHF 0.4 Mio). Development of a public health and research focused platform for Switzerland to share whole genome sequencing data of pathogens, recently expanding to COVID-19. Role: Principal investigator – study design, coordination, whole genome sequencing, data analysis (see www.spsp.ch and http://p3.snf.ch). In collaboration with all virology and bacteriology clinical microbiology institutes of Basel (A. Egli & H.H. Hirsch), CHUV (G. Greub), HUG (J. Schrenzel & L. Kaiser), Inselspital (S. Leib), Vetsuisse (V. Perreten & R. Stephan), Zurich (R. Zbinden & A. Trkola / M. Huber) and technical support of SIB (A. Lebrand). Active.

(v) High-resolution shotgun metagenomics approach for the detection of food-associated bacteria and source tracking of surface contaminations (Bangerter Rhyner-funded grant, CHF 0.08 Mio). Developing a metagenomic-based protocol for rapid assessment of food samples using Nanopore sequencing. Role: Principal investigator – project coordination, collection of samples, supervision of Post-doctoral fellow. In collaboration with the cantonal laboratory in Basel (C. Bagutti). Active.

(vi) Skin metagenomics as a predictive marker for graft-versus-host disease after allogeneic stem cell transplantation. (Bangerter Rhyner funded grant, CHF 0.08 Mio). Developing and exploring skin microbiome assessment as a risk predicting tool for graft-versus-host disease. Role: Co-investigator, laboratory management of the study, supervision of  postdoctoral fellow for sequencing. In collaboration with the haematology (J. Halter) and dermatology departments (S. Müller). Active.

(vii) Rapid diagnosis of virulence and antibiotic resistance through mass spectrometry and machine learning (ETH grant on personalized medicine, CHF 0.5 Mio). Exploring machine learning in order to rapidly detect drug resistance in MALDI-TOF MS spectra from pathogens. Role: Co-PI, study design, coordination, clinical validation, data analysis. In collaboration with ETH Zürich group (Borgwardt) (see https://bsse.ethz.ch/research/Research-Projects-on-Personalised-Medicine.html). Active. 

(viii) Development of various novel diagnostic devices for detection of antibiotic drug resistance (NRP72-funded) – (i) microfluidic device for microbes in collaboration with ETH Zurich group (P. Dittrich) and (ii) fast assessment of antibiotic resistance in bacteria by using nanomechanical arrays (cantilever) in collaboration with Physic department of University of Basel (E. Meyer). Role: Co-applicant – study design, clinical expertise and performance, biobanking/sampling (see www.nrp72.ch and http://p3.snf.ch). Active. 

(ix) NCCR AntiResist (CHF 17 Mio). Research program to develop new environment for antibiotic discovery. Role: co-applicant, member of the executive board – study design, data coordination from the hospital. In collaboration with the Biozentrum of the University of Basel (C. Dehio, U. Jenal, D. Bumann) and multiple other research groups including University of Zurich and ETH Zurich (see http://www.snf.ch/en/researchinFocus/nccr/antiresist and http://p3.snf.ch). Role: Coapplicant and clinical data officer. Active. 

(x) Biobanking at the University Hospital and beyond (SNF Biolink-funded, CHF 0.62 Mio). Role: Co-applicant – study-design, coordination of microbiological samples and IT developments. Finished.

(xi) Precision Microbiota Engineering for Child Health (BRCCH-funded). Role: Partner – coordination of sequencing of bacterial genomes, coordination of bacterial strains. Partner with groups from ETH Zurich (E. Slack) and Biozentrum (M. Diard) (see https://brc.ch/multiinvestigator-projects/). Active. 

National Collaborations

• Biozentrum, University of Basel (Prof. Dr. Urs Jenal, Prof. Dr. Richard Neher, Prof. Dr. Médéric Diard http://www.biozentrum.unibas.ch/
• D-BSSE, ETH Zurich (Prof. Dr. Karsten Borgwardt, https://www.bsse.ethz.ch/mlcb, Prof. Dr. Joerg Stelling, http://www.csb.ethz.ch/, Prof. Dr. Petra Dittrich, https://dittrich.ethz.ch/)
• Department of Environmental Systems Science, ETH Zurich, Prof. Dr. Alex Hall, http://www.pe.ethz.ch/research.html, Prof. Dr. Sebastian Bonhoeffer, http://www.tb.ethz.ch/
• Institute of Microbiology, ETH Zürich, Prof. Dr. Wolf-Dietrich Hardt, https://micro.biol.ethz.ch/research/hardt.html
• Department of Health Sciences and Technology, ETH Zurich, Prof. Dr. Emma Slack, https://ifnh.ethz.ch/research/food-immunology.html, Prof. Nicholas Bokulich, https://fsb.ethz.ch/, 
• University Hospital Basel, Prof. Dr. Manuel Battegay, Infectious Diseases and Hospital Epidemiology, Prof. Dr. Nina, Khanna, Infectious Diseases and Hospital Epidemiology, PD Dr. Michael Osthoff, Internal, Medicine, Prof. Dr. Martin Siegemund, Intensive Care Medicine, Prof. Dr. Sarah Tschudin-Sutter, Infectious Diseases and Hospital Epidemiology, Prof. Dr. Andreas Widmer, Infectious, Diseases and Hospital Epidemiology, Prof. Roland Bingisser, Department of Emergency, Medicine, Prof. Christian Nickel, Department of Emergency Medicine, PD Dr. Simon Müller, Dermatology, Prof. Dr. Stefano Bassetti, Internal Medicine, https://www.unispital-basel.ch/
• Swiss Tropical and Public Health Institute, Dr. Penelope Vounatsou, Dr. Pascale Vonäsch
• University of Basel, Department Umweltwissenschaften, Prof Dr. Rita Schneider-Sliwa, Abteilung Humangeographie / Stadt- und Regionalforschung, https://humgeo.unibas.ch/
• Cantonal laboratory, City of Basel, Dr. Silvia Gautsch, Dr. Claudia Bagutti, http://www.kantonslabor.bs.ch/
• University of Zurich, Prof. Roger Stephan, Veterinary Bacteriology
• Cantonal laboratory, BaselLand, Dr. Peter Brodmann, https://www.baselland.ch/politik-und-behorden/direktionen/volkswirtschafts-undgesundheitsdirektion/lebensmittelsicherheit-und-veterinarwesen
• Swiss Pathogen Surveillance Platform, Aitana Lebrand, SIB, Gilbert Greub, CHUV, Dominique Blanc, CHUV, Jacques Schrenzel, HUG, Vincent Perreten, VetSuisse, University of Bern, Roger Stephan, VetSuisse, University of Zurich, Richard Neher, Biozentrum, University of Basel

Companies: 
Dr. Valentin Pflüger, Mabritec, Riehen, http://www.mabritec.com/ and Dr. Olivier Dubuis, Viollier, https://www.viollier.ch/en/

International Collaborations

• Ben Gurion University of the Negev, Israel, Prof. Jacob Moran-Gilad; https://morangiladlab.com/pi/ 
• Global Capnocytophaga Consortium, Els M. Broens (University of Utrecht, Netherlands), Francesco Renzi (University of Namur, Belgium), Kirstine K. Soegaard (Universitetshospital Aarhus, Denmark)

Transmission of clinically relevant pathogens:

Infectious diseases cause significant morbidity and mortality. Understanding the sources, transmission and dynamics of pathogens is key to identifying and preventing outbreaks.

Viral transmission models

We use human influenza viruses and most recently SARS-CoV-2 to study transmission events in the context  of local outbreaks and global transmission. For both viruses, we have established whole genome sequencing and analysis pipelines and humoral immune assays. Together with our collaborating partners, we explore transmission events and spatio-temporal dynamics across the Basel region, and investigate viral evolution in clinically relevant contexts, such as treatment of hospitalized patients. 

Bacterial transmission models 

Bacterial pathogens of interest include multi-drug resistant bacteria such as ESBL- and Carbapenemase-producing and hypervirulent Enterobacteriaceae, Clostridioides difficile, and Methicillin resistant Staphylococcus aureus, as well as interesting clinical outbreaks. We use whole genome sequencing (WGS; Illumina and Oxford Nanopore) and metagenomic approaches in order to describe genetic relatedness and evolution within hosts. Specific projects include: 

• Developing metagenomic tools to determine MDR colonization status of patients directly from swabs. Bioinformatic tools will be developed to monitor microbiota changes over time within the patient during hospitalisation.
• Investigating the transmission dynamics of ESBL plasmids in Enterobacteriaceae: in collaboration with colleagues from ETH Zurich, we analyse plasmid transmission efficacy using in vitro and mouse models. More information is available here. 
• The Swiss Pathogen Surveillance Platform (www.spsp.ch): collaborating with the Universities and University Hospitals of Basel, Geneva and Lausanne, VetSuisse (University of Bern and Zurich) and the Swiss Institute for Bioinformatics, we are constructing an interoperable molecular and classical epidemiological database for WGS and metadata sharing for (multidrug resistant) pathogens. More information is available at the NRP72 website (www.nrp72.ch). 

Retention and Displacement of ESBL E. coli
Antibiotic resistance is a severe threat to contemporary medicine. Therefore, we urgently need effective approaches to fight multidrug resistant pathogenic bacteria such as multidrug resistant E. coli. In 2017 the World Health Organization (WHO) classified the E. coli strains which express extended spectrum beta lactamases (ESBL E. coli), priority 1 due to their rise world-wide. So far there are no effective means to prevent the spread of ESBL E. coli. Our project develops a radically new approach to fight ESBL E. coli. We hypothesize that ESBL E. coli can be efficiently displaced from the patient’s gut by applying well-defined microbials. Our approach roots in the observation that >50% of the colonized people
spontaneously lose their colonizing ESBL E. coli strains within 6-18 months. We assume it to be due to the incidental ingestion of competitive, ideally pan-sensitive strains. Such strains are natural microbials and could provide a powerful means to stop the spread of ESBL E. coli.

• Firstly, we will perform a prospective observational single centre clinical cohort study to monitor ESBL E. coli colonization dynamics in the human gut. We enrolled 40 travelers to India and sampled their stool and blood at well-defined timepoints over one year. On these samples we are going to deploy shotgun metagenomics to obtain a broad and yet detailed picture of microbial dynamics over time and of the motility of genetic elements within the entire gut microbiota. This will give us an unprecedented picture of how microbe-microbe interactions shape the microbial successions in the gut, and on how the fading of ESBL strains over time takes place. Importantly, shotgun metagenomics will allow us to narrow down key displacer-pansensitive E.coli candidates for further testing. In parallel we will generate a systematic strain collection of ESBL E. coli isolates and their corresponding pan-sensitive E. coli strains. Each strain will undergo whole genome sequencing.
• In the second phase we will test our reconstructed colonisation dynamics, by testing the displacing ability of single candidate isolates in a mouse model. These pre-clinical experiments will establish whether pan-sensitive E. coli isolates from human participants can swiftly replace ESBL E. coli within the mammalian gut. Such natural strains  would be the basis for future decolonization trials in ESBL E. coli positive humans. 
• Finally our findings on ESBL displacement in humans and mice will be used to produce a colonization-displacement model that could serve to explain and possibly predict ESBL displacement, ultimately providing concrete indications for clinicians for an effective treatment.

Applications to routine diagnostics 

We translate our findings to improve  the speed, precision, and cost efficacy of routine diagnostic tools, and to reduce transmission of virulent and resistant pathogens.A key focus is on Matrix assisted laser desorption ionization - time of flight mass spectrometry (MALDI-TOF MS), which has revolutionized bacterial species identification in microbiological diagnostics. Despite the  success of this technique, important challenges remain, such as detection directly from patient specimens and correct identification of closely related species. Specific projects include:

• Developing protocols to use MALDI-TOF MS directly from human specimens such as positive blood cultures and urine samples. We have recently shown that rapid direct identification of positive blood cultures significantly reduces the time for correct antibiotic treatment and improved the patient outcome. 
• Investigating the ability of MALDI TOF MS to distinguish between Klebsiella species. In a national and international consortium of routine diagnostic laboratories, we have elucidated species specific markers, compared whole genome sequences from our labs and databases, and predicted ribosomal protein masses which lie between 2,000 and 20,000 Daltons which can be detected by MALDITOF MS.
• Improving MALDI-TOF MS protocols , as the accuracy and resolution of MALDI-TOF is highly dependent on the spectra quality. We are currently conducting an international external quality assessment (EQA) including more than 30 laboratories around the globe to explore the factors associated with improved quality. 
• Determining antibiotic resistance categories (susceptible or resistant) directly from MALDI-TOF MS spectral data with a machine learning based approach 
• Determining the phylogenetic characteristics of invasive and non-invasive E. coli isolates from patients using MALDI-TOF MS and whole genome sequencing data, aiming to enable earlier relevant clinical interventions.