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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-American research team deciphers evolution of pathogenic Acinetobacter strains
Hospital-acquired infections (HAIs) are often particularly difficult to treat because the pathogens have developed resistance to common antibiotics. The bacterium Acinetobacter baumannii is particularly dreaded in this respect, and research is seeking new therapeutic approaches to combat it. To look for suitable starting points, an international team led by bioinformaticians at Goethe University Frankfurt has compared thousands of genomes of pathogenic and harmless Acinetobacter strains. This has delivered clues about which properties might have made A. baumannii a successful pathogen – and how it might possibly be combated.
FRANKFURT/ST. LOUIS. Each year, over 670,000 people in Europe fall ill through pathogenic bacteria that exhibit antibiotic resistance, and 33,000 die of the diseases they cause. Especially feared are pathogens that are resistant to several antibiotics at the same time. Among them is the bacterium Acinetobacter baumannii, which is today dreaded above all as a “hospital superbug": up to five percent of all hospital-acquired bacterial infections are caused by this germ alone.
A. baumannii is right at the top of a list of candidates for which, according to the World Health Organization (WHO), new therapies must be developed. This is because the pathogen – due to a flexible genome – easily acquires new antibiotic resistance. At the same time, infections are not only occurring more and more outside the hospital environment but also leading to increasingly severe progression. However, a prerequisite for the development of new therapeutic approaches is that we understand which properties make A. baumannii and its human pathogenic relatives, grouped in what is known as the Acinetobacter calcoaceticus-baumannii (ACB) complex, a pathogen.
A team led by bioinformatician Professor Ingo Ebersberger from Goethe University Frankfurt/ LOEWE Centre for Translational Biodiversity Genomics (LOEWE-TBG) has now reached a milestone in this understanding. The team is composed of members of Research Unit 2251 of the German Research Foundation and other national and international partners, among them scientists of Washington University School of Medicine, St Louis, USA.
For their analysis, the team made use of the fact that a large proportion of the members of the Acinetobacter genus are harmless environmental bacteria that live in water or on plants or animals. Thousands of complete genome sequences both of these as well as of pathogenic Acinetobacter strains are stored in publicly accessible databases.
By comparing these genomes, the researchers were able to systematically filter out differences between the pathogenic and the harmless bacteria. Because the incidence of individual genes was not particularly conclusive, Ebersberger and his colleagues concentrated on gene clusters, that is, groups of neighbouring genes that have remained stable during evolution and might form a functional unit. “Of these evolutionarily stable gene clusters, we identified 150 that are present in pathogenic Acinetobacter strains and rare or absent in their non-pathogenic relatives," says Ebersberger, summing up. “It is highly probable that these gene clusters benefit the pathogens' survival in the human host."
Among the most important properties of pathogens is their ability to form protective biofilms and to efficiently absorb micronutrients such as iron and zinc. And indeed, the researchers discovered that the uptake systems in the ACB group were a reinforcement of the existing and evolutionary older uptake mechanism.
Particularly exciting is the fact that the pathogens have evidently tapped a special source of energy: they can break down the carbohydrate kynurenine produced by humans, which as a messenger substance regulates the innate immune system. The bacteria apparently kill two birds with one stone in this way. On the one hand, breaking down kynurenine supplies them with energy, and on the other hand, they could possibly use it to deregulate the host's immune response.
Ebersberger is convinced: “Our work is a milestone in understanding what's different about pathogenic Acinetobacter baumannii. Our data are of such a high resolution that we can even look at the situation in individual strains. This knowledge can now be used to develop specific therapies against which, with all probability, resistance does not yet exist."
Publication: Bardya Djahanschiri, Gisela Di Venanzio, Jesus S. Distel, Jennifer Breisch, Marius Alfred Dieckmann, Alexander Goesmann, Beate Averhoff, Stephan Göttig, Gottfried Wilharm, Mario F. Feldman, Ingo Ebersberger: Evolutionarily stable gene clusters shed light on the common grounds of pathogenicity in the Acinetobacter calcoaceticus-baumannii complex. PLOS Genetics (2022) DOI: 10.1371/journal.pgen.1010020 https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1010020
Scanning electron micrograph of a cluster of Gram-negative, immobile bacteria of the Acinetobacter baumannii species. Photo: Janice Carr
Professor Ingo Ebersberger
Institute of Cell Biology and Neuroscience
Goethe University Frankfurt
Tel.: +49 69 798 42112