NEWSLETTER Special Edition | 02.2018Medical Microbiology & Infection Prevention

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Microbes in Health & Disease Science Day 2017

© MMB Newsletter Special Edition 02.2018 • Medical Microbiology and Infection Prevention © MMB Newsletter Special Edition 02.2018 • Medical Microbiology and Infection Prevention

Research in the UMCG is performed under the umbrella of Healthy Ageing. I.e. the science of understanding the mechanisms of how to remain or to get again healthy. The research program “Microbes in Health & Disease” focuses exactly on this very question, the role of microorganisms in maintaining health or causing disease. An important paradigm here is that the causative agents for health and disease are transmittable from host to host and disease can spread.

Microbe-associated communicable health is subject to novel research. This comprises different model-microbes, different transmission ways and requires research on fundamental, clinical and translational aspects. There is no doubt.

Research on how to avoid communicable disease or how to foster health is clearly preventive and important for a sustainable and systemic health-care approach. This will be our contribution to the development of the Aletta Jacobs School of Public Health.

Prof.dr. Alex Friedrich, Chair and Head of the Department Medical Microbiology and Infection Prevention

The fourth Science Day of Microbes in Health and Disease (MHD) was held on November 14th, 2017. Twelve PhD students from different departments united in MHD presented (prelimary) results of their research projects. The topics ranged from basic to translational to clinical studies thereby nicely reflecting the diversity of MHD. A keynote lecture was given by Prof.dr. Lude Franke. He gave a very interesting lecture titled ‘Future of Genetics’ in which he presented strategies to reuse available data, innovative computational methods and software to increase statistical power to finally predict more accurately gene functions helping to gain insight in development of diseases. As usual the members of the Organizing Committee rated the presentations from the PhD students independently and compared their final scores. Because of the very close scores of the best three presenters, the final ranking was

discussed within the Organizing Committee. This resulted in Laura Palma Medina being the winner of this year’s competition. Her study aimed to understand the intracellular adaptations of Staphylococcus aureus in lung epithelial cells to generate more alternatives for the treatment of these infections in the respiratory tract. Her presentation was very dynamic and easy to understand for a broad audience. Overall, the PhD candidates were able to give excellent presentations. The lively discussions were particularly appreciated. Although session chairs sometimes had to terminate the discussion to keep up with the tight time schedule the Organizing Committee strongly encourages junior scientist to engage in the scientific debate of the MHD science day. We would like to welcome Mathieu Bolhuis to the Organizing Committee for the next year. He will take over from Jan-Willem Alffenaar, who

Alex W. FriedrichChair of Medical Microbiology and Infection Prevention

Head of departmentUniversity Medical Center Groningen

Tel: +31.(0)50.361 3480

nieuwsbrief.mmb@umcg.nl

Web: www.mmb-umcg.nl

This newsletter is published by the Department of Medical Microbiology and Infection Prevention of the University Medical Center Groningen.

The editorial staff consists of: Alex W. Friedrich, Edwina Doting en Carolien Doorenbos.

alex.friedrich@umcg.nlm.h.e.doting@umcg.nlc.r.c.doorenbos@umcg.nl

© 2018 Realisation & Design by IDEART-Agentur.de

Impressum

has been in the Organizing Committee for the past three years. The Organizing Committee would like to thank Jolanda Oldengarm-Leidelmeijer for her never-ending enthusiasm and taking the lead in orga-nizing this day, that made the fourth Science Day to a success. As the Organizing Committee we are looking forward to the next (Fifth!) Science Day in 2018.

Dr. Jan-Willem Alffenaar, mw. Jolanda Oldengarm- Leidelmeijer, drs. Randy Poelman, dr. John Rossen, organizing committee

Figure: The Organizing Committee together with best speaker Laura: Jolanda Oldengarm-Leidelmeijer, Jan Willem Alffenaar, John Rossen, Laura Palma Medina and Randy Poelman

Microbes in Health & Disease Science Day UMCG

Prevention-related Research

© MMB Newsletter Special Edition 02.2018 • Medical Microbiology and Infection Prevention © MMB Newsletter Special Edition 02.2018 • Medical Microbiology and Infection Prevention

CHAIR: Natacha Monge Gomes do Couto, PhD Researcher and post-doc in Medical Microbiology, Genomics for Infection Prevention

SPeAkeRS:Gabriela Tapia Calle, Medical Microbiology, Vaccinology 'A cell-based system to assess responses to vaccines in vitro'

Anne Gomes, Medical Microbiology, Genomics for Infection Prevention 'Sonication of heart valves detects more bacteria in infective endocarditis'

erley Lizarazo, Medical Microbiology, Genomics for Infection Prevention 'Shotgun metagenomics as a tool for the rapid diagnosis and genotyping of dengue'

Laura Palma Medina, Medical Microbiology, Molecular Bacteriology 'The inside job: adaptations of Staphylococcus aureus during lung infection'

CHAIR: Randy Poelman, MSc PhD student Medical Microbiology, Clinical Virology

SPeAkeRS: Randy Poelman, Medical Microbiology, Clinical Virology 'Diagnostic stewardship: from patient perspective to European surveillance of enterovirus D68'

Anet Veringa, Clinical Pharmacy and Pharmacology 'The additional value of repeated voriconazole trough concentration determination during antifungal treatment'

keynote lecture: Prof.dr. Lude Franke ‘Future of Genetics’

CHAIR: Mathieu Bolhuis, PharmD, PhD Principal Investigator (PI) Clinical Pharmacy and Pharmacology

SPeAkeRS:Arianna Pranger, Clinical Pharmacy and Pharmacology 'Reduced moxifloxacin exposure in male tuberculosis patients and the need for monitoring in early stages of treatment'

Arezoo Shajiei, Intensive Care Unit 'Reducing antibiotic resistance with procalcitonin in critically ill patients'

Maaike van den Beld, Medical Microbiology, Genomics for Infection Prevention 'Incidence, infection risks and outcomes of infections with entero-invasive bacteria Shigella and Escherichia coli: results from a cross-sectional study'

CHAIR: Silvia Garcia Cobos, PhD Researcher in Medical Microbiology, Genomics for Infection Prevention

SPeAkeRS: Yingying Cong, Cell Biology 'Unveiling the coronavirus life cycle'

Ana Carolina Cruz Campos, Medical Microbiology, Genomics for Infection Prevention 'Urinary Tract Infections (UTI) caused by Escherichia coli in Hospitals of Rio de Janeiro, Brazil'

John Arboleda Alzate, Medical Microbiology, Experimental Virology 'Cell death during dengue virus infection: a blessing or a curse?'

Session 1

Session 2

Session 3

Session 4

Chairs and speakers of the MHD Science Day

© MMB Newsletter Special Edition 02.2018 • Medical Microbiology and Infection Prevention © MMB Newsletter Special Edition 02.2018 • Medical Microbiology and Infection Prevention

Natacha Monge Gomes do Couto, PhD, chair of session 1Researcher and post-doc in Medical Microbiology, Genomics for Infection Prevention

Session 1 was dedicated to the development of new diagnostic tools for the detection of microbial pathogens (bacteria and viruses) as well as to the development of new therapeutic tools. As stated by Anne and Erley, new diagnostic tools are needed for infections that are challenging to diagnose, like infective endocarditis, and for infections that can be caused by a variety of pathogens, like febrile-illness in patients in the tropics, that can be caused by Dengue virus. On the other hand, Gabriela and Laura showed innovative methodologies to generate alternatives for treatment against major pathogens, like Influenza and Staphylococcus aureus.

Gabriela Tapia Calle MSc, PhD student Medical Microbiology, Vaccinology Email: m.g.tapia.calle@umcg.nl

Prof.dr. A.L.W. Huckriede

Philip Born, Wouter Hinrichs, Dept. Pharmacy, RUG

Clinical trials are time-consuming and expensive and are a bottleneck in vaccine development. Therefore we develop an in vitro system based on stimulation of PBMCs (peripheral blood mononuclear cells) with vaccine candidates and adjuvants and evaluation of their responses.To evaluate T cell responses, PBMCs are treated with FLT3 (a hematopoietic cytokine) and stimulated using different influenza vaccine formulations and influenza peptides. After 10 days, activation, cytotoxic potential and production of IFNγ are measured. We demonstrated that the used influenza vaccines and peptides can induce cytotoxic activity and IFNγ production in human cells. Our model can therefore be used to assess vaccine candidates.

A PBMC-based system to assess responses to vaccines in vitro

Anne Gomes MSc, PhD student Medical Microbiology, Genomics for Infection Prevention Email: a.gomes@umcg.nl

Prof.dr. Bhanu Sinha, dr. Sander van Assen, dr. Peter Paul van Geel, dr. Andor Glaudemans

IDENTICAL, improved diagnosis of endocarditis and its therapy with a focus on prosthetic material (February 15th 2014 / June 30th 2018).

In collaboration with Marleen van Oosten, Kasper Bijker, Kathleen Boiten, Elisa Salomon, Sigrid Rosema, John Rossen, Ehsan Natour, Yvonne Douglas, Greetje Kampinga, Sander van Assen, Bhanu Sinha.

Reaching a microbiological diagnosis in infective endocarditis is crucial for optimal treatment. However, in 10-49% of cases of intracardiac infection microbiological tests are false-negative because of biofilm formation and prior antimicrobial therapy. To mobilize bacteria from biofilm, sonication is used. This is a method that uses ultrasonic waves, by which bacterial cell structures are not significantly damaged. Our protocol for sonication of heart valves that is followed by centrifugation of the sonication fluid, resulted in an increase of detected and cultured pathogens. Contamination was limited with this protocol. Therefore, it is regarded a useful addition to microbiological diagnostics in infective endocarditis.

Sonication of heart valves detects more bacteria in infective endocarditis

Session 1

© MMB Newsletter Special Edition 02.2018 • Medical Microbiology and Infection Prevention © MMB Newsletter Special Edition 02.2018 • Medical Microbiology and Infection Prevention

erley Lizarazo MSc, PhD student Medical Microbiology, Genomics for Infection PreventionEmail: e.f.lizarazo.forero@umcg.nl

Prof.dr. A.W. Friedrich, dr. A. Tami, dr. J.W.A. Rossen, prof. Maria E. GrilletGenomics for Infection Prevention (EPITROP research group, Epidemiology of Tropical and Infectious Diseases)

In collaboration with Natacha Couto, Erwin Raangs, Maria Vincenti-Gonzalez, Sarah Bethencourt (Universidad de Carabobo, Venezuela), Thomas Jaenisch (Heidelberg University, Germany)

Dengue identification and genotyping through shotgun metagenomics is possible directly from patients’ sera or plasma with an identity as high as 99%. The whole workflow is approximately two times faster than what is needed for classical genotyping through standard isolation and identification. A superior resolution on the dynamics of dengue epidemics is given by the phylogenetic analyses of complete genome sequences, compared to partial genome sequencing. Moreover, shotgun metagenomics allows the detection and discrimination of other viruses causing similar clinical presentations, namely Chikungunya and Zika.

Shotgun metagenomics as a tool for the rapid diagnosis and genotyping of dengue

Laura Marcela Palma Medina MSc, PhD student Medical Microbiology, Molecular BacteriologyEmail: l.m.palma.medina@umcg.nl

Prof.dr. Jan Maarten van Dijl and prof.dr. Uwe Völker, University of Greifswald

In collaboration with Petra Hildebrandt, Stephan Michalik, Manuela Gesell Salazar, Kristin Surmann, Henrike Pförtner.

Staphylococcus aureus is a Gram-positive bacterium that has the ability to infect different tissues of our body ranging from mild skin infections to severe illnesses like pneumonia. S. aureus can invade non-professional phagocytic cells, as a mechanism to avoid the immune response and to spread to other tissues.

To generate more alternatives for the treatment of S. aureus infections in the respiratory tract, we study intracellular adaptations of this pathogen in lung epithelial cells. We found that upon internalization, S. aureus replicates intracellularly and causes lysis of the host cells. During later stages of infection, the bacteria enter a dormant state which is related to persistence. Furthermore, S. aureus also changes its behavior depending on the polarization of the epithelial cells, taking advantage of the low polarized state after injury.

The inside job: adaptations of Staphylococcus aureus during lung infection

© MMB Newsletter Special Edition 02.2018 • Medical Microbiology and Infection Prevention © MMB Newsletter Special Edition 02.2018 • Medical Microbiology and Infection Prevention

Randy Poelman MSc, PhD student Medical Microbiology, Clinical Virology Email: r.poelman@umcg.nl

Prof.dr. H.G.M. Niesters and prof.dr. A.W. Friedrich

In collaboration with Certe, Izore, Isala, GGD Groningen (REGIOtype), RIVM (TypeNED) and >40 European national reference and diagnostic laboratories (EUROtype), connected through the ESCV network as well as the European CDC.

Enterovirus D68 causes not only mild respiratory illness, but also severe neurological disease. To expand currently availa-ble knowledge, we provide a (Sanger) Sequencing service for Northern Netherlands (REGIOtype), which is also part of the national surveillance for enterovirus (TypeNED) and serves as a fundament for the European collaborative on enterovirus diagnostics and surveillance, particularly enterovirus D68 (EUROtype).Findings within several European countries represent a low (but fortunately increasing) awareness among clinicians of this disease and of the value of sending the right sample to test for, as well as a lack of proper diagnostics and/or sequencing.

Diagnostic stewardship: from patient perspective to European surveillance of enterovirus D68

Anet Veringa PharmD, PhD student Clinical Pharmacy and PharmacologyEmail: a.veringa@umcg.nl

Prof.dr. J.G.W. Kosterink, prof.dr. T.S. van der Werf and dr. J.W.C. AlffenaarZonMw study group

In collaboration with Roger J. Brüggemann, Lambert F.R. Span, Bart J. Biemond, Mark G.J. de Boer, Edwin R. van den Heuvel, Saskia K. Klein, Doris Kraemer, Monique C. Minnema, Niek H.J. Prakken, Bart J.A. Rijnders, Jesse J. Sven, Paul Verweij, Mariëlle J. Wondergem, Paula Ypma, Nicole Blijlevens, Jos G.W. Kosterink, Tjip S. van der Werf, Jan-Willem C. Alffenaar

Invasive aspergillosis is one of the most common invasive fungal infections and is seen in patients with a haematological malignancy or patients who received a hematopoietic stem cell transplant. Voriconazole is a first line antifungal agent for the treatment of invasive aspergillosis. The standard weight-based dosing of voriconazole often results in sub-therapeutic or toxic serum concentrations.

We studied the effect of therapeutic drug monitoring (TDM) of voriconazol on patient outcome and found that it is not superior to the standard weight-based dose regimen. However, several studies associated the voriconazol trough concentration with its efficacy and safety, so TDM could be performed in some patients.

The additional value of repeated voriconazole trough concentration determination during antifungal treatment

Randy Poelman, MSc, chair of session 2PhD student Medical Microbiology, Clinical Virology

The MHD science day is not just a yearly event where PhD candidates have the opportunity to show their current research. It is a day where everyone shares their different perspectives. Bringing together fundamental, clinical and epidemiological areas is something that does not happen all year long. The second session of the day was an example of this, showing translational research that covered all previously mentioned areas. From fungi to viruses, from microbiology to genetics.

The keynote speaker, Professor Lude Franke from the Genetics department, showed a glimpse of (future) genetic research. Tremendous oppor-tunities were shown, and one question always keeps me interested: how to bring all our knowledge to the place where it is most valuable to the most important stakeholder? The patient.

Session 2

© MMB Newsletter Special Edition 02.2018 • Medical Microbiology and Infection Prevention © MMB Newsletter Special Edition 02.2018 • Medical Microbiology and Infection Prevention

Mathieu Bolhuis, PharmD, PhD, chair of session 3Principal Investigator (PI) Clinical Pharmacy and Pharmacology

In the third session of the MHD Science Day three diverse presentations were held. The first presentation of the session provided some insights in the individualization of tuberculosis treatment using the fluoroquinolone moxifloxacin. In the second presentation the use of procalcitonin as a marker was discussed. In both presentations, albeit in very different infections and patient populations, the final goal of the research was to improve treatment outcomes and survival rates. The final presentation provided epidemiological insight in Shigella and EIEC from a cross-sectional study. This study will provide tools for the optimization of guidelines.

Arianne Pranger MSc, PhD student Clinical Pharmacy and PharmacologyEmail: a.pranger@umcg.nl

Prof.dr. J.G.W. Kosterink, dr. J.W.C. Alffenaar, Clinical Pharmacy and Pharmacology (UMCG), prof.dr.T.S. van der Werf, Pulmonary Disease and Tuberculosis (UMCG)

Moxifloxacin is a critical component of the current rifampicin and multidrug-resistant tuberculosis regimen. However, low moxifloxacin exposure is frequently observed and is associated with acquired drug resistance and a slow response to treat-ment. We hypothesized that as tuberculosis patients have improving health status over time during tuberculosis treatment, moxifloxacin exposure may change over time as well. To optimize moxifloxacin treatment for tuberculosis based on pharmacokinetic and pharmacodynamic principles, we are developing an optimal sampling strategy and analytical methods for advanced laboratory methods in resource-limited settings in order to determine moxifloxacin exposure in body fluids.

Reduced moxifloxacin exposure in male tuberculosis patients and the need for monitoring in early stages of treatment

Arezoo ShajieiMSc, MPhil, PhD student Medical Microbiology and Intensive Care UnitEmail: a.shajiei@umcg.nl

Dr. Maarten Nijsten, dr. Annemieke Oude Lansink, prof.dr. Anne Marie de Smet – Intensive Care Unit (UMCG), PronkjewailDr. Dylan de Lange, Intensive Care Unit (UMC Utrecht)Thermo Fisher Company

The key for improving survival rates of sepsis lies in early diagnosis and appropriate antibiotic treatment as well as reducing antibiotic overtreatment. Procalcitonin (PCT) is a biomarker that is more specific for severe bacterial infection than C-reactive protein and lactate. There is evidence suggesting that the use of PCT for assessing patients with suspected sepsis leads to improved early recognition of bacterial infection. Moreover, several trials, including the large Dutch SAPS-trial, have demonstrated that monitoring the subsequent decrease of PCT during recovery results in a safe and considerable reduction in antibiotic treatment.

Reducing antibiotic resistance with procalcitonin in critically ill patients

Maaike van den Beld PhD student Medical Microbiology, Genomics for Infection PreventionEmail: m.j.c.van.den.beld@umcg.nl

Prof.dr. A.W. Friedrich, dr. J.W.A. Rossen – Department of Medical Microbiology, UMCG, GroningenDr. A.M.D. Kooistra-Smid – Department of Medical Microbiology, Certe, GroningenDr. F.A.G. Reubsaet – Centre for Infectious Disease Control, National Institute for Public Health and the Environment, RIVM, Bilthoven

In collaboration with Sigrid Rosema, Monika Chlebowicz, Mithila Ferdous, Kai Zhou, Richard de Boer and Evert van Zanten, and 15 Medical Microbiological Laboratories throughout the Netherlands and their adjacent Public Health Services.

Shigella and entero-invasive Escherichia coli (EIEC) are bacteria that cause a similar disease and are difficult to distinguish in the laboratory. Most patients suffer from diarrhea. The highest risk for infection is traveling. To gain insight in diagnostics, incidence, disease outcome, transmission and socio-economic consequences of infections with EIEC and Shigella, an Invasive Bacteria E. coli-Shigella Study (IBESS) has started in January 2016. The outcomes of this study will also provide tools for evidence-based optimization of national guidelines regarding infectious diseases caused by Shigella and EIEC. Shigella sonnei, Shigella flexneri and EIEC were isolated from stool most frequently in the Netherlands.

Incidence, infection risks and outcomes of infections with entero-invasive bacteria Shigella and Escherichia coli: results from a cross-sectional study

Session 3

© MMB Newsletter Special Edition 02.2018 • Medical Microbiology and Infection Prevention © MMB Newsletter Special Edition 02.2018 • Medical Microbiology and Infection Prevention

Silvia Garcia Cobos, PhD, chair of session 4Researcher in Medical Microbiology, Genomics for Infection Prevention

Infectious diseases are a leading cause of death worldwide, and pathogenic bacteria and viruses are the most common causative agents. The mosquito-borne viral disease Dengue is widespread throughout the tropics and it is spreading to new areas, in addition many cases are underreported or misclassified. Coronavirus epidemics such as SARS and MERS demonstrated that new infectious diseases can rapidly spread and adapt to different hosts over time. Infections due to multidrug resistant bacteria are of major concern and are a challenge in public health nowadays. Urinary tract infections - health-care associated or community acquired – caused by resistant E.coli are very common and can be recurrent. Understanding the pathogenesis, cycle life and epidemiology of these microorganisms is crucial to control and prevent their trans-mission and to develop effective therapeutic treatments.

Yingying CongMSc, PhD student Cell BiologyEmail: y.cong@umcg.nl

Prof.dr. Fulvio Reggiori, prof.dr. Anke Huckriede

Coronaviruses (CoV) are enveloped viruses with a single-stranded positive RNA genome and cause numerous pathologies in mammals. The nucleocapsid protein (N) of CoV is a multifunctional protein that is known to interact with replication and transcription complexes (RTCs). Our study will focus on which component of RTC is responsible for N-RTCs interaction and whether this interaction has benefit to coronavirus replication. Conclusions so far:

• CoV N protein associates with RTCs mainly through nsp3 binding.• Multiple domains in the N protein are required for its interaction with nsp3.• Nsp3-binding domains of the N protein are required for its association to RTCs.• Blocking of the recruitment of N protein to RTCs has a negative effect on CoV replication.

Unveiling the coronavirus life cycle

Session 4

Figure: Break in the blue patio

© MMB Newsletter Special Edition 02.2018 • Medical Microbiology and Infection Prevention © MMB Newsletter Special Edition 02.2018 • Medical Microbiology and Infection Prevention

Ana Carolina da Cruz Campos PhD student Medical Microbiology, Genomics for Infection Prevention Email: a.c.da.cruz.campos@umcg.nl

Prof.dr. Alex W. Friedrich, dr. John W.A. Rossen and dr. Jerome R. Lo Ten Foe Medical Microbiology and Infection Prevention (UMCG)

Paulo Damasco en Ana Claudia Rosa

Urinary tract infections (UTIs) are the second most common health-care associated infections. The number of UTIs caused by multidrug-resistant bacteria, mainly Extended-spectrum β-lactamase producing (ESBL) E. coli, has increased and this can be caused due to spread of multidrug-resistant clones. Whole genome sequencing (WGS) allows molecular characterization of pathogens including identification of virulence genes, drug resistance genes and clones responsible for more complicated infections. The high-risk ST131/025 clone is spread throughout the world, including Brazil. The presence of this clone represents a challenge to physicians, not only due to the multidrug-resistance feature, but also because it is associated with more complicated infections.

Urinary Tract Infections (UTI) caused by Escherichia coli in hospitals of Rio de Janeiro, Brazil

John F. Arboleda Alzate MSc, PhD student Medical Microbiology, Experimental Virology Email: j.f.arboleda.alzate@umcg.nl

Dr. I.A. Rodenhuis-Zybert, prof.dr. J.M. Smit

Alberto Aquilar Briseño, Silvio Urcuqui-Inchima Clinical outcomes of dengue virus (DENV) infection vary from a mild self-limited flu-like illness to a potentially fatal severe dengue. High viral titers and prolonged or exacerbated production of immunomodulatory molecules represent main contributing factors in the pathogenesis of severe disease. We characterized cell death mechanisms induced in the course of DENV infection in monocytes, which are cells representing not only the key sentinels of the immune system but also main targets of DENV replication. We found a biphasic activation of lytic cell death processes in the course of DENV infection. Our data suggest a complex but key role of the RIPK1/3 axis and/or lytic cell death in DENV pathogenesis.

Cell death during dengue virus infection: a blessing or a curse?