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The human pathogenic bacterium Bartonella henselae serves international research team as model organism for highly resistant infectious agents
Using bacteria of the Bartonella henselae species, researchers from Goethe University, Frankfurt University Hospital, the Paul Ehrlich Federal Institute for Vaccines and Biomedicines in Langen, and the University of Oslo demonstrated for the first time that antibodies can prevent certain surface proteins of bacterial pathogens from entering host cells. The findings are important for the development of new drugs against highly resistant infectious agents.
FRANKFURT. Infections, especially those with highly resistant pathogens, pose a significant threat to human health. It is dangerous when pathogens manage to colonize the organism and subsequently cause severe infections. The first step in such an infection always consists of the pathogens attaching themselves to the host cells' surface. From here, the infections spread, resulting, for example, in infections of deeper tissue layers and organs.
A group of scientists surrounding Prof. Volkhard Kempf from Frankfurt University Hospital's Institute of Microbiology and Hospital Hygiene has now succeeded in blocking this adhesion mechanism in a bacterium, thereby preventing the infection of host cells. For this purpose, the researchers examined the pathogen Bartonella henselae, usually causing cat scratch disease. Transmitted by cats, the disease mainly affects young children, whose symptoms include swollen and hardened lymph nodes around the site of infection – usually following a scratch or bite injury caused by infected cats.
Bartonella bacteria infect so-called endothelial cells, which line the blood vessels. Via their surface protein Bartonella adhesin A (BadA), they attach themselves to a protein (fibronectin) of the so-called "extracellular matrix", a network of protein fibers that lie on top of the endothelial cells.
To determine which parts of the BadA protein are important in the bacterial adhesion process, the researchers equipped Bartonella bacteria with various genetically modified BadA variants, among others, and then analyzed the extent to which these variants were still able to bind fibronectin. Once it was clear which BadA segments were responsible for the binding, the team produced antibodies against them, using cell culture experiments to show for the first time that such antibodies can prevent infection by such bacteria.
Prof. Volkhard Kempf explains: "Bartonella henselae is not a very dangerous pathogen, and in most cases, cat scratch disease does not require any specific medical treatment. However, for us Bartonella henselae is a very important model organism for far more dangerous pathogens such as Acinetobacter baumannii, a serious pathogen that usually causes wound infection or pneumonia and often shows resistance to several last-choice antibiotics. The BadA protein of Bartonella henselae belongs to the so-called 'trimeric autotransporter adhesins', which are also responsible for adhesion to human cells in Acinetobacter and a number of other pathogens. A drug-induced blocking of these adhesins is therefore a promising novel and future approach to combat dangerous bacterial infections."
The research was supported by the Viral and Bacterial Adhesin Network Training (ViBrANT) program; a HORIZON 2020 research and innovation program of the European Union under the Marie Skłodowska-Curie grant agreement; the Robert Koch Institute, Berlin, Germany; the “PROXYDRUGS" project of the Federal Ministry of Education and Research; as well as the German Research Foundation DFG.
Publication: Arno Thibau, Diana J. Vaca, Marlene Bagowski, Katharina Hipp, Daniela Bender, Wibke Ballhorn, Dirk Linke, Volkhard A. J. Kempf: Adhesion of Bartonella henselae to Fibronectin Is Mediated via Repetitive Motifs Present in the Stalk of Bartonella Adhesin A. https://journals.asm.org/doi/10.1128/spectrum.02117-22
Background: How bacteria adhere to cells: Basis for the development of a new class of antibiotics (22 June 2022) https://www.goethe-university-frankfurt.de/74958144?search=kempf
Caption: Adhesion of Bartonella henselae (blue) to human blood vessel cells (red). The bacterium's adhesion to the host cells could be blocked with the help of so-called “anti-ligands". Credit: https://www.mdpi.com/2075-4418/11/7/1259
Professor Volkhard A. J. Kempf
Director of the Institute of Medical Microbiology and Hospital Hygiene
University Hospital Frankfurt
Goethe University Frankfurt
Phone: +49 (0)69 6301–5019
Bartonella bacteria use certain proteins – conserved pathomechanism in other bacterial species
Researchers from University Hospital Frankfurt and Goethe University Frankfurt have unravelled how bacteria adhere to host cells and thus taken the first step towards developing a new class of antibiotics.
FRANKFURT. The adhesion of bacteria to host cells is always the first and one of the decisivesteps in the development of infectious diseases. The purpose of this adhesion by infectious pathogens is first to colonize the host organism (i.e., the human body), and then to trigger an infection, which in the worst case can end fatally. Precise understanding of the bacteria's adhesion to host cells is a key to finding therapeutic alternatives that block this critical interaction in the earliest possible stage of an infection.
Critical interaction with the human protein fibronectin
In collaboration with other researchers, scientists from University Hospital Frankfurt and Goethe University Frankfurt have now explained the exact bacterial adhesion mechanism using the human-pathogenic bacterium Bartonella henselae. This pathogen causes “cat-scratch disease", a disease transmitted from animals to humans. In an international collaborative project led by the Frankfurt research group headed by Professor Volkhard Kempf, the bacterial adhesion mechanism was deciphered with the help of a combination of in-vitro adhesion tests and high-throughput proteomics. Proteomics is the study of all the proteins present in a cell or a complex organism.
The scientists have shed light on a key mechanism: the bacterial adhesion to the host cells can be traced back to the interaction of a certain class of adhesins – called “trimeric autotransporter adhesins" – with fibronectin, a protein often found in human tissue. Adhesins are components on the surface of bacteria which enable the pathogen to adhere to the host's biological structures. Homologues of the adhesin identified here as critical are also present in many other human-pathogenic bacteria, such as the multi-resistant Acinetobacter baumannii, which the World Health Organization (WHO) has classified as the top priority for research into new antibiotics.
State-of-the-art protein analytics were used to visualize the exact points of interaction between the proteins. In addition, it was possible to show that experimental blocking of these processes almost entirely prevents bacterial adhesion. Therapeutic approaches that aim to prevent bacterial adhesion in this way could represent a promising treatment alternative as a new class of antibiotics (known as “anti-ligands") in the constantly growing domain of multi-resistant bacteria.
The research work was funded as part of an Innovative Training Network (“ViBrANT: Viral and Bacterial Adhesin Network Training") under the Marie Skłodowska-Curie Actions (MSCA) of the European Union's HORIZON 2020 research and innovation programme.
The scientific paper has been published in
the prestigious journal “Microbiology Spectrum" of the American Society of
Microbiology (ASM) and was acknowledged as “Paper of the Month" by the German
Society for Hygiene and Microbiology (DGHM) on 18 June 2022.
Publication: Vaca, D. J., Thibau, A., Leisegang, M. S., Malmström, J., Linke, D., Eble, J. A., Ballhorn, W., Schaller, M., Happonen, L., Kempf, V. A. J.; Interaction of Bartonella henselae with Fibronectin Represents the Molecular Basis for Adhesion to Host Cells; Microbiology Spectrum, 18 April, 2022. https://doi.org/10.1128/spectrum.00598-22
https://www.kgu.de/fileadmin/redakteure/Presse/Bilder_Pressmitteilungen/2022/Vaca_Diana_Jaqueline.jpgCaption: First author of the study: Diana Jaqueline Vaca, Institute of Medical Microbiology and Hospital Hygiene at University Hospital Frankfurt. Photo: University Hospital Frankfurt
Adhesion of Bartonella henselae (blue) to human blood vessel cells (red). The bacterium's adhesion to the host cells could be blocked with the help of what are known as “anti-ligands".
Professor Volkhard A. J. Kempf
Director of the Institute of Medical Microbiology and Hospital Hygiene
University Hospital Frankfurt
Tel.: +49 (0)69 6301–5019
Editor: Christoph Lunkenheimer, Press Officer, Staff Unit Communication at Universitätsklinikum Frankfurt, Phone: +49 (0)69 6301–86442, firstname.lastname@example.org
German Research Foundation extends project aimed at combating multi-resistant Acinetobacter baumannii strains
FRANKFURT. Cases of multi-resistant bacteria in hospitals have increased dramatically in recent years and the health system faces tremendous problems as a result. Alongside “old acquaintances”, such as Staphylococcus aureus (MRSA) or Klebsiella pneumonia, another pathogen has now arrived on the scene: Acinetobacter baumannii. In order to find new weapons for the fight against this aggressive germ, in 2014 the German Research Foundation established a Research Unit led by Goethe University Frankfurt which has now been extended for a further three years.
Infections with Acinetobacter baumannii are often fatal due to this bacterium’s increasing antibiotic resistance. In some European countries, over 90 percent of isolates no longer respond to antibiotic therapy. Particularly worrying is the fact that the pathogen is continuing its rapid advance throughout the whole world.
In order to obtain results in this situation that can be put to use as quickly as possible in clinical practice, natural scientists and physicians are working closely together in the Research Unit “Adaptation and Persistence of Acinetobacter baumannii”. Several institutes at Goethe University Frankfurt – Molecular Microbiology & Bioenergetics, Medical Microbiology & Infection Control, the Institute of Cell Biology & Neuroscience and the Institute of Biochemistry – are involved in the project together with the Robert Koch Institute and the universities in Cologne and Regensburg.
“We have achieved something quite unique: We use patient isolates, sequence their genome and analyse their pathogenic properties, which are then characterized with regard to countermeasures,” explain Professor Volker Müller, microbiologist, and Professor Volkhard Kempf, microbiologist and physician, who are the Research Unit’s two spokespersons. It has already been possible to identify first virulence traits by means of this approach.
The researchers know meanwhile what the bacterium feeds on, how it survives stress, how it adheres to animate and inanimate surfaces and how it withstands antibiotics. This knowledge enables them to test new targets for deactivating the bacterium. They discovered, for example, that bacteria are no longer able to trigger infections if you take away their ability to synthesise a certain sugar (trehalose). The research team is now working hard to shed light on this sugar’s biosynthesis process so that inhibitors can be developed.
The evaluators found this work so convincing that the German Research Foundation has not only extended the project but also increased its budget. The work undertaken in future will produce new answers to the question of how this increasingly threatening bacterium can be treated.
A picture can be downloaded from: www.uni-frankfurt.de/70620941
Caption: Petri dish with colonies of the dangerous hospital pathogen Acinetobacter baumannii.
Photo: Goethe University Frankfurt
Further information: Professor Volker Müller, spokesperson of Research Unit 2251, Molecular Microbiology & Bioenergetics, Faculty of Biological Sciences, Riedberg Campus, Tel.: +49(0)69-798-29507; email@example.com.
Professor Volkhard Kempf, University Hospital Frankfurt, Institute for Medical Microbiology and Infection Control, Faculty of Medicine, Niederrad Campus, Tel.: +49(0)69- 6301-5019, firstname.lastname@example.org, http://www.bio.unifrankfurt.de/51172482
EU funds further three networks for doctoral training at Goethe University Frankfurt
FRANKFURT. The European Union is funding three new projects - Innovative Training Networks (ITN) within the Marie Sklodowska-Curie Programme - for structured doctoral training at Goethe University Frankfurt. Such projects are very attractive for universities because they are open to all scientific topics and focus on basic research.
For the CLOUD-MOTION project coordinated by atmospheric researcher Professor Joachim Curtius, Goethe University Frankfurt has been awarded funding of € 500,000. This is a follow-up project from two previous doctoral researcher networks successfully coordinated by Professor Curtius since 2008.
In CLOUD-MOTION, doctoral researchers at 10 European institutions will investigate cloud formation from aerosols and ice particles in the atmosphere and their influence on the climate. A key focus is the comparison of intact areas of the atmosphere with those polluted as a result of human activities. Research work is based on experiments in a “cloud chamber” at CERN, the European Organization for Nuclear Research, in which different situations in the atmosphere can be simulated under laboratory conditions.
The ViBrANT Network, of which Goethe University Frankfurt is a member, is an interdisciplinary team of European infection researchers leading in their field worldwide. The network is working together for a better understanding of how viruses and bacteria attach to host cells. This will form the basis for developing highly specific diagnostic procedures, whereby one of the main priorities is the development of new diagnostic detection methods for multi-resistant pathogens. The 15 doctoral researchers will become acquainted with universities and industrial partners in seven European countries during their training and this will teach them how to convert findings from basic research as rapidly as possible into usable technologies that benefit patients with infectious diseases. € 500,000 have been made available for doctoral researchers at Goethe University Frankfurt.
Goethe University Frankfurt is also involved in the UbiCODE doctoral network, which is searching for new diagnostic markers and drug targets in the ubiquitin system. This small protein found throughout the body forms unexpectedly diverse and complex chains. The contribution of these chains to the regulation of protein functions and cellular quality control is, however, far from being fully understood. Malfunctions in this system can lead to diseases such as cancer, neurodegeneration, inflammatory conditions and multiple infections. Goethe University Frankfurt’s share of the funding is € 250,000.
With the approval of the three new ITNs, the University is continuing it success of the past years in this funding line. In 2016, five new projects started work. 18 ITNs are currently underway at Goethe University Frankfurt.
Further information: CLOUD-MOTION: Prof. Dr. Joachim Curtius, Department of Atmospheric and Environmental Sciences, Faculty of Geosciences and Geography, Riedberg Campus, Tel.: +49 (0) 69 798 40258, email@example.com
ViBrANT: Prof. Dr. Volkhard Kempf, Institute of Medical Microbiology and Infection Control, Faculty of Medicine, Niederrad Campus, Tel.: +49 (0) 69 6301-5019, firstname.lastname@example.org
UbiCODE: Prof. Dr. Ivan Dikic, Dr. Kerstin Koch, Institute of Biochemistry II, Faculty of Medicine, Niederrad Campus, Tel.: +49 (0)69 6301-84250, K.Koch@em.uni-frankfurt.de
Researchers from Goethe University discover a new clinical biomarker to improve treatment of leukaemia
Because it is impossible to predict which acute myeloid leukaemia (AML) patients will benefit, all patients are routinely treated with chemotherapy although only some will respond to the treatment. Researchers from Goethe-University Frankfurt have now discovered a novel biomarker that enables the detection of therapy responders and non-responders with high accuracy. In addition, their research reveals new hope for patients who currently cannot be effectively treated.
The anti-cancer drug cytarabine provides the basis of chemotherapies directed against AML. Cytarabine needs to be activated in cancer cells by the addition of phosphate groups to exert its anti-cancer effects. Prof Jindrich Cinatl (Institut für Medizinische Virologie, Goethe-Universität, Acting Director: Prof Volkhard Kempf) investigated with his research group (funded by the Frankfurter Stiftung fürkrebskranke Kinder) cytarabine-resistant AML cells from the Resistant Cancer Cell Line (RCCL) collection (www.kent.ac.uk/stms/cmp/RCCL/RCCLabout.html) that he runs together with Prof Martin Michaelis (University of Kent, Canterbury, UK). ProfCinatl discovered that the toxicity of cytarabine against AML cells correlates with the expression of the cellular enzyme SAMHD1, which enables to predict the sensitivity of AML cells to cytarabine.
Following this initial finding, a consortium led by Prof Cinatl together with Prof Oliver Keppler (who moved from the Institut für Medizinische Virologie, Goethe-Universität to Ludwig-Maximilians-Universität, München during the project) showed that SAMHD1 removes the phosphate residues from the active form of cytarabine and thereby reverses it into its inactive state. In a cooperation with clinicians (led by Prof Hubert Serve, Medizinische Klinik II, Goethe-Universität) it was shown that SAMHD1 levels determined in leukaemia cells also enabled the prediction of the response of AML patients to cytarabine-based chemotherapies with high accuracy. This introduces SAMHD1 as clinical biomarker that can guide cytarabine-based chemotherapies only to such patients that are very likely to respond and spares patients who are unlikely to respond from toxic side effects. In addition, the Frankfurt-led team showed that inhibition of SAMHD1 effectively sensitises cytarabine-resistant AML cells to cytarabine-based chemotherapies, opening future prospects for the treatment of patients for whom currently no effective therapy exists.
The research was published in the journal Nature Medicine on 19th December 2016 and can be found here: