Host-pathogen interactions, bacterial metabolism and adhesion to biotic and abiotic surfaces
Nosocomial pathogens such as Candida albicans, Clostridioides difficile, Enterococcus spp, Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus are common in our environment or might even be a part of our ‘normal’ physiological flora. These bacteria/fungi are usually well tolerated by our body without creating an inflammatory response, if certain areas are colonized, but they may turn into life-threatening pathogens when allowed to enter into different parts of our body or if our immune system is compromised. Many of them are able to adhere to and to form biofilms (i.e. multilayered structures of microbial cells embedded into an extracellular matrix) on implanted medical devices such as artificial joints, central or peripheral venous catheters, and dental implants. Such biofilms are of particular concern, as cells released by these biofilms may serve as starting point for other infections such as bacteremia. Of the nearly 2 million healthcare-associated infections reported by the Centers for Disease Control (CDC) per year for the United States since the beginning of the 21st century, more than 50% can be attributed to indwelling medical devices1. It is thus of utmost importance to understand how these microbial pathogens interact with implanted medical devices in the human setting, and how they manage to subvert our immune system. Research at IMMH is trying to address both topics by studying regulatory systems affecting infectivity and immune evasion in mammal hosts, and by investigating the initial adhesion events between pathogenic microorganisms and biotic/abiotic surfaces by Atomic Force Microscopy-based Single Cell Force Spectroscopy.
1VanEpps, J.S. and Younger, J.G. (2016) Implantable Device-Related Infection. Shock 46:597-608. DOI: 10.1097/shk.0000000000000692
Regulatory systems affecting infectivity and immune evasion of bacteria in mammal hosts (Bischoff, Jung)
A prominent member of the group of nosocomial bacteria is Staphylococcus aureus, a common colonizer of our nasopharyngeal area and the skin, and at the same time a feared opportunistic pathogen in the healthcare setting. Especially in immunocompromised people, S. aureus is able to cause live-threatening diseases such as endocarditis, osteomyelitis, and sepsis. The Gram-positive bacterium is equipped with a large armamentarium of virulence factors and a sophisticated network of regulatory molecules allowing it to rapidly respond to environmental changes encountered within the host during the infection process. In this part of our research activities at IMMH, we are interested in identifying and characterizing regulatory factors and phosphorylation systems involved in pathogenesis of S. aureus. We are specifically interested in regulators that link virulence factor synthesis with the metabolic activity of the bacterial cell. Another major focus of our staphylococcal research are protein kinase/phosphatase systems and their impact on infectivity. Potential genes of interest will be inactivated by genetic engineering, and resulting mutants characterized in a variety of in vitro (i.e. biofilm assays, growth kinetic studies, metabolomics, transcriptomics, and cell culture-based adhesion and invasion/persistence studies) and in vivo assays (i.e. murine infection models). Another major pillar of this part of IMMH research are bacterial secretion factors, with a special focus on how the host recognizes them, and which immune response(s) are triggered. Scientists and students interested in this topic are warmly welcome to collaborate with us in this exciting research field. If you are interested, please contact Markus Bischoff or Philipp Jung via e-mail (markus.bischoff @uks.eu / Philipp.jung@uks.eu) or phone (+49 6841 162 3963).
Selected publications by members of the research group covering this topic:
- Benthien et al. (2022) The transcription factor SpoVG is of major importance for biofilm formation of Staphylococcus epidermidis under in vitro conditions, but dispensable for in vivo biofilm formation. Int J Mol Sci. 23:3255. doi.org/10.3390/ijms23063255
- Aljohmani et al. (2022) Pseudomonas aeruginosa triggered exosomal release of ADAM10 mediates proteolytic cleavage in trans. Int J Mol Sci. 23:1259. DOI: 10.3390/ijms23031259
- Elhawy et al. (2021) The phosphoarginine phosphatase PtpB from Staphylococcus aureus is involved in bacterial stress adaptation during infection. Cells 10:645. DOI: 10.3390/cells10030645
- Pätzold et al. (2021) Impact of the histidine-containing phosphocarrier protein HPr on carbon metabolism and virulence in Staphylococcus aureus. Microorganisms 9:466. DOI: 10.3390/microorganisms9030466
- Gunaratnam et al. (2019) ClpC affects the intracellular survival capacity of Staphylococcus aureus in non-professional phagocytic cells. Sci Rep. 9:16267. DOI: 10.1038/s41598-019-52731-3
- Bufe et al. (2019) Bacterial MgrB peptide activates chemoreceptor Fpr3 in mouse accessory olfactory system and drives avoidance behaviour. Nat Commun. 10:4889. DOI: 10.1038/s41467-019-12842-x
- Gannoun-Zaki et al. (2018) PtpA, a secreted tyrosine phosphatase from Staphylococcus aureus, contributes to virulence and interacts with Coronin-1A during infection. J Biol Chem. 293:15569-15580. DOI: 10.1074/jbc.RA118.003555
- Eisenbeis et al. (2018) The Staphylococcus aureus Extracellular Adherence Protein Eap Is a DNA Binding Protein Capable of Blocking Neutrophil Extracellular Trap Formation. Front Cell Infect Microbiol. 8:235. DOI: 10.3389/fcimb.2018.00235
Funding sources:
- Deutsche Forschungsgemeinschaft (DFG)
- UdS/HIPS Tandem
Group members:
- Hannah Benthien, cand. med.
- Mohamed I. Elhawy, PhD candidate
- Karin Hilgert, laboratory technician
- Öznur Köse, Masterstudentin
- Swarnali Kundu, PhD candidate
- Vanessa Sturtz, Bachelorstudentin
- Ben Wieland, PhD candidate
- Philipp Jung, PhD
- Markus Bischoff, PhD
Initial adhesion events between pathogenic microorganisms and biotic/abiotic surfaces studied by Atomic Force Microscopy-based Single Cell Force Spectroscopy (Jung, Bischoff)
Investigating the early steps of pathogen adhesion to host structures or medical devices is an important task of medical basic research. Once adhered to a substrate, pathogens have developed numerous strategies to strengthen that initial contact and entering a sessile stadium. In this scope, several bacterial species, like Staphylococcus aureus, Coagulase-negative staphylococci or Enterococcus spp. are capable to form microbial biofilms, in which cells are embedded in an extracellular protein or polysaccharide layer rendering the pathogens less susceptible to antibiotic treatment and the host immune response. In contrast, fungal biofilms, as exemplified by Candida albicans, are usually characterized by growing, interweaving hyphae after transitioning its growth phase from a yeast-based dissemination stage to a hyphae stage mediating pathogenicity. Protozoan parasites, on the other hand, have developed complex organelles mediating adhesion and pathogenicity. This aspect is currently investigated for the microtubule-based adhesive disk of Giardia duodenalis (synonymous: Giardia intestinalis, Giardia lamblia), which is believed to function similar to a suction cup.
Our initial adhesion studies focus mainly on Atomic Force Microscopy (AFM), which has emerged as a tremendously versatile tool to study mechanical properties and adhesion forces of organisms at a cellular and subcellular level. We are utilizing AFM-based Single Cell Force Spectroscopy to characterize adhesion properties of diverse pathogens described above in various approaches. Adhesion properties of eukaryotic cells to naïve or functionalized surfaces is another major pillar of this part of IMMH research activities, which is mainly addressed by Fluid-FM technology. We are happy to collaborate with interested colleagues and students. If you are interested, please feel free to contact Philipp Jung or Markus Bischoff via e.mail (philipp.jung @uks.eu / markus.bischoff@uks.eu) or phone (+49 6841 162 3904).
Selected publications by members of the research group covering this topic:
- Mischo et al. 2022. Hydroxyapatite pellets as versatile model surfaces for systematic adhesion studies on enamel: A force spectroscopy case study. ACS Biomater Sci Eng. 8:1476-1485. DOI: 10.1021/acsbiomaterials.1c00925
- Spengler et al. (2021) Using Knock-Out Mutants to Investigate the Adhesion of Staphylococcus aureus to Abiotic Surfaces. Int J Mol Sci. 22:11952. DOI: 10.3390/ijms222111952
- Gunaratnam et al. (2021) Quantification of the adhesion strength of Candida albicans to tooth enamel. Microorganisms 9:2213. DOI: 10.3390/microorganisms9112213
- Jung et al. (2021) T cell stiffness is enhanced upon formation of immunological synapse. Elife 10:e66643. DOI: 10.7554/eLife.66643
- Gunaratnam et al. (2020) Human blood plasma factors affect the adhesion kinetics of Staphylococcus aureus to central venous catheters. Sci Rep. 10:20992. doi: 10.1038/s41598-021-89018-5.
- Jung et al. (2020) Candida albicans adhesion to central venous catheters: Impact of blood plasma-driven germ tube formation and pathogen-derived adhesin. Virulence 11:1453-1465. DOI: 10.1080/21505594.2020.1836902
- Maikranz et al. (2020) Different binding mechanisms of Staphylococcus aureus to hydrophobic and hydrophilic surfaces. Nanoscale 12:19267-19275. DOI: 10.1039/d0nr03134h
- Spengler et al. (2019) Strength of bacterial adhesion on nanostructured surfaces quantified by substrate morphometry. Nanoscale 11:19713-19722. DOI: 10.1039/c9nr04375f
Funding sources:
- Deutsche Forschungsgemeinschaft (DFG)
- UdS/HIPS Tandem
Group members:
- Gubesh Gunaratnam, PhD candidate
- Clara Mischo, cand. med.
- Ben Wieland, PhD candidate
- Markus Bischoff, PhD
- Philipp Jung, PhD
