Projects & Collaborations 9 foundShow per page10 10 20 50 Heterogeneity of host, pathogen, and their interaction mechanisms during urinary tract infections Research Project | 1 Project MembersImported from Grants Tool 4701214 Causes and consequences of phenotypic subpopulation formation during bacterial biofilm development Research Project | 1 Project MembersBiofilms are surface-bound spatially structured microbial communities, which are now considered to be the most abundant form of bacterial life on Earth. For many microbial commensals and pathogens, biofilm formation is an essential part of their lifecycle, so that biofilms are ubiquitous in soil, in aqueous environments, and on surfaces presented by plants and animals. The aim of this project is to determine the principles and mechanisms that govern the formation of subpopulations in biofilms. This will be achieved by comprehensively identifying subpopulations during the growth of biofilms from a single cell into a macrocolony, followed by determining the mechanisms that underlie the formation of subpopulations. Furthermore, we will comprehensively characterize the subpopulations and their properties. My interdisciplinary research group is in a unique position to perform the proposed work on biofilm subpopulations, due to our previous development of single-cell imaging and image analysis techniques for biofilms, due to our existing computational data analysis and simulation techniques, and due to our expertise in basic molecular microbiology and biofilm research. Together, this expertise allows my group to identify all subpopulations, and to determine how the subpopulations develop, respond to stresses, and contribute to the properties of the whole biofilm population. Ultimately, the proposed project will result in a comprehensive mechanistic understanding of phenotypic subpopulations during biofilm development. Charakterisierung der Mechanismen die zur Antibiotikatolerenz in Biofilmen von Vibrio cholerae führen Research Project | 1 Project MembersBacteria have the ability to form spatially structured multicellular communities, called biofilms. Biofilms are considered to be the dominant form of bacterial life on our planet and they are well-known to promote microbial survival under harmful environmental conditions. For example, biofilm-associated cells display increased tolerance towards stress treatment when compared to planktonic bacteria, which complicates biofilm removal in clinical settings. Thus, stress tolerance presents an important multicellular function of biofilms with clear fitness benefits, however, the underlying regulatory processes and biophysical mechanisms are unclear. In this proposal, we aim to close this gap by studying the emergent stress tolerance of biofilms formed by the major human pathogen Vibrio cholerae. More generally, this project will provide insights into biofilm development, intercellular communication, and the regulatory principles underlying bacterial communities. HFSPO Fellowship Takuya Ohmura Research Project | 1 Project MembersIn their natural environment and during infections, bacteria are commonly organized in surface-attached communities termed biofilms, which are held together by a self-produced extracellular matrix. These biofilms can develop from single cells into macroscopic three-dimensional communities with characteristic morphology and cellular differentiation, reminiscent of eukaryotic multicellular development. Recently, single-cell level live-imaging of complete biofilm development has become possible, which now permits the experimental testing of detailed simulation predictions for biofilm development, and places the grand challenge of a quantitative and predictive understanding of biofilm development within reach. The key ingredients of the required simulations are the cell-cell interaction mechanisms and behavioral states of cells, yet both are generally unknown. To overcome this barrier, I will develop techniques for spatiotemporal transcriptome data generation and analysis during Vibrio cholerae biofilm development, which will allow me to obtain spatiotemporal maps of cellular interaction mechanisms and cellular states. These spatiotemporal maps will then be used as input for individual-based simulations I will develop, to identify which of the vast possibilities of cellular interactions and properties are necessary and sufficient for biofilm development. This interplay of experiments and simulations based on spatiotemporal transcriptome data and single-cell microscopy will ultimately not only identify the key cellular interaction mechanisms, but also the cellular interaction principles that are required irrespective of the underlying molecular mechanisms. Interaction mechanisms of Vibrio cholerae biofilms and macrophages Research Project | 1 Project MembersThe interactions between V. cholerae and macrophages are unclear, both in terms of the mechanisms and functions. By combining molecular techniques for the manipulation of V. cholerae and macrophages, as well as advanced transcriptome and imaging techniques, we will determine the molecular toolkits, mechanisms, and strategies that govern the interaction dynamics of V. cholerae and macrophages. This project will provide a foundational understanding of the infectious life cycle of V. cholerae within the host. Zusammensetzung und Funktion von Vibrio cholerae Biofilmen auf humanen Makrophagen Research Project | 1 Project MembersCholera is a devastating diarrheal disease, caused by the bacterium Vibrio cholerae . Although V. cholerae induces an inflammatory response during infection, it is currently unclear how V. cholerae cells interact with the innate immune system. Focusing on the interaction of V. cholerae with macrophages, we discovered a surprising interaction process in preliminary work: V. cholerae cells form biofilms on the surface of macrophages, followed by macrophage death. In the proposed project, we will determine the key mechanisms underlying the formation, matrix composition, and function of biofilms on macrophages, and how macrophage death occurs during the interaction with V. cholerae . This project will provide a major new insight into the interaction mechanisms of V. cholerae with the human immune system. BIOFAGE / Interaction Dynamics of Bacterial Biofilms with Bacteriophages Research Project | 1 Project MembersBiofilms are antibiotic-resistant, sessile bacterial communities that occupy most moist surfaces on Earth and represent a major mode of bacterial life. Another common feature of bacterial life is exposure to viral parasites (termed phages), which are a dominant force in bacterial population control throughout nature. Surprisingly, almost nothing is known about the interactions between biofilm-dwelling bacteria and phages. This proposal is designed to fill this gap using a combination of novel methodology, experimental systems, and mathematical modeling. We have recently developed a new microscopic imaging technique that allows us to image and track all individual cells and their gene expression inside biofilms. First, we will use this technique for tracking the population dynamics of bacteria and phages within biofilms at single cell resolution. By genetically manipulating bacterial hosts and their phages, and by varying environmental conditions, we will investigate the fundamental biological and physical determinants of phage spread within biofilm communities. Second, we will study how biofilms respond to phage attack on both intra-generational and evolutionary time scales, focusing in particular on proximate response mechanisms and the population dynamics of phage-resistant and phage-susceptible cells as a function of biofilm spatial structure. Lastly, we will combine our novel insights to engineer phages that manipulate the composition of biofilm communities, either by subtraction of particular bacterial species or by addition of novel phenotypes to existing biofilm community members. Altogether, the proposed research promises to uncover the major mechanistic and evolutionary elements of biofilm-phage interactions. This combined work will greatly enrich our knowledge of microbial ecology and motivate novel strategies for bacterial biofilm control, an increasingly urgent priority in light of widespread antibiotic resistance. PHYMOT - Physics of Microbial Motility Research Project | 1 Project MembersSuspensions of swimming bacteria display collective motion when the density of bacteria increases. These collective movements take the form of large groups of cells that transiently move in the same direction, which break up into swirls, forming intermittent vortex-like structures. The cell-cell interaction mechanisms that underlie the emergence of bacterial collective motion in two- and three-dimensional suspensions are unclear. Using genetics, we will modify bacterial cells such that physical parameters of bacterial motility and bacterial cell surface-adhesiveness are altered, e.g. by changing the cellular aspect ratio, flagella length, flagellar rotation speed, and surface adhesion expression. These genetic modifications will alter key cellular properties that are predicted by theoretical models to change the bacterial cell-cell scattering interactions. These mutants will provide a basis for experimentally dissecting the contributions of different cellular properties to bacterial collective movement. NCCR AntiResist: New approaches to combat antibiotic-resistant bacteria Umbrella Project | 32 Project MembersAntibiotics are powerful and indispensable drugs to treat life threatening bacterial infections such as sepsis or pneumonia. Antibiotics also play a central role in many other areas of modern medicine, in particular to protect patients with compromised immunity during cancer therapies, transplantations or surgical interventions. These achievements are now at risk, with the fraction of bacterial pathogens that are resistant to one or more antibiotics steadily increasing. In addition, development of novel antimicrobials lags behind, suffering from inherently high attrition rates in particular for drug candidates against the most problematic Gram-negative bacteria. Together, these factors increasingly limit the options clinicians have for treating bacterial infections. The overarching goal of NCCR AntiResist is to elucidate the physiological properties of bacterial pathogens in infected human patients in order to find new ways of combatting superbugs. Among the many societal, economic, and scientific factors that impact on the development of alternative strategies for antibiotic discovery, our limited understanding of the physiology and heterogeneity of bacterial pathogens in patients ranks highly. Bacteria growing in tissues of patients experience environments very different from standard laboratory conditions, resulting in radically different microbial physiology and population heterogeneity compared to conditions generally used for antibacterial discovery. There is currently no systematic strategy to overcome this fundamental problem. This has resulted in: (i) suboptimal screens that identify new antibiotics, which do not target the special properties of bacteria growing within the patient; (ii) an inability to properly evaluate the efficacy of non-conventional antibacterial strategies; (iii) missed opportunities for entirely new treatment strategies. This NCCR utilizes patient samples from ongoing clinical studies and establishes a unique multidisciplinary network of clinicians, biologists, engineers, chemists, computational scientists and drug developers that will overcome this problem. We are excited to merge these disciplines in order to determine the properties of pathogens infecting patients, establish conditions in the lab that reproduce these properties and utilize these in-vitro models for antimicrobial discovery and development. In addition, clinical-trial networks and the pharmaceutical industry have major footprints in antimicrobial R&D. Exploiting synergies between these players has great potential for making transformative progress in this critical field of human health. This NCCR maintains active collaborations with Biotech SMEs and large pharmaceutical companies with the goal to: accelerate antibiotic discovery by providing relevant read-outs for early prioritization of compounds; enable innovative screens for non-canonical strategies such as anti-virulence inhibitors and immunomodulators; identify new antibacterial strategies that effectively combat bacteria either by targeting refractory subpopulations or by synergizing with bacterial stresses imposed by the patients' own immune system. This NCCR proposes a paradigm shift in antibiotic discovery by investigating the physiology of bacterial pathogens in human patients. This knowledge will be used to develop assays for molecular analyses and drug screening under relevant conditions and to accelerate antibacterial discovery, improve treatment regimens, and uncover novel targets for eradicating pathogens. Through this concerted effort, this NCCR will make a crucial and unique contribution to winning the race against superbugs. 1 1
Heterogeneity of host, pathogen, and their interaction mechanisms during urinary tract infections Research Project | 1 Project MembersImported from Grants Tool 4701214
Causes and consequences of phenotypic subpopulation formation during bacterial biofilm development Research Project | 1 Project MembersBiofilms are surface-bound spatially structured microbial communities, which are now considered to be the most abundant form of bacterial life on Earth. For many microbial commensals and pathogens, biofilm formation is an essential part of their lifecycle, so that biofilms are ubiquitous in soil, in aqueous environments, and on surfaces presented by plants and animals. The aim of this project is to determine the principles and mechanisms that govern the formation of subpopulations in biofilms. This will be achieved by comprehensively identifying subpopulations during the growth of biofilms from a single cell into a macrocolony, followed by determining the mechanisms that underlie the formation of subpopulations. Furthermore, we will comprehensively characterize the subpopulations and their properties. My interdisciplinary research group is in a unique position to perform the proposed work on biofilm subpopulations, due to our previous development of single-cell imaging and image analysis techniques for biofilms, due to our existing computational data analysis and simulation techniques, and due to our expertise in basic molecular microbiology and biofilm research. Together, this expertise allows my group to identify all subpopulations, and to determine how the subpopulations develop, respond to stresses, and contribute to the properties of the whole biofilm population. Ultimately, the proposed project will result in a comprehensive mechanistic understanding of phenotypic subpopulations during biofilm development.
Charakterisierung der Mechanismen die zur Antibiotikatolerenz in Biofilmen von Vibrio cholerae führen Research Project | 1 Project MembersBacteria have the ability to form spatially structured multicellular communities, called biofilms. Biofilms are considered to be the dominant form of bacterial life on our planet and they are well-known to promote microbial survival under harmful environmental conditions. For example, biofilm-associated cells display increased tolerance towards stress treatment when compared to planktonic bacteria, which complicates biofilm removal in clinical settings. Thus, stress tolerance presents an important multicellular function of biofilms with clear fitness benefits, however, the underlying regulatory processes and biophysical mechanisms are unclear. In this proposal, we aim to close this gap by studying the emergent stress tolerance of biofilms formed by the major human pathogen Vibrio cholerae. More generally, this project will provide insights into biofilm development, intercellular communication, and the regulatory principles underlying bacterial communities.
HFSPO Fellowship Takuya Ohmura Research Project | 1 Project MembersIn their natural environment and during infections, bacteria are commonly organized in surface-attached communities termed biofilms, which are held together by a self-produced extracellular matrix. These biofilms can develop from single cells into macroscopic three-dimensional communities with characteristic morphology and cellular differentiation, reminiscent of eukaryotic multicellular development. Recently, single-cell level live-imaging of complete biofilm development has become possible, which now permits the experimental testing of detailed simulation predictions for biofilm development, and places the grand challenge of a quantitative and predictive understanding of biofilm development within reach. The key ingredients of the required simulations are the cell-cell interaction mechanisms and behavioral states of cells, yet both are generally unknown. To overcome this barrier, I will develop techniques for spatiotemporal transcriptome data generation and analysis during Vibrio cholerae biofilm development, which will allow me to obtain spatiotemporal maps of cellular interaction mechanisms and cellular states. These spatiotemporal maps will then be used as input for individual-based simulations I will develop, to identify which of the vast possibilities of cellular interactions and properties are necessary and sufficient for biofilm development. This interplay of experiments and simulations based on spatiotemporal transcriptome data and single-cell microscopy will ultimately not only identify the key cellular interaction mechanisms, but also the cellular interaction principles that are required irrespective of the underlying molecular mechanisms.
Interaction mechanisms of Vibrio cholerae biofilms and macrophages Research Project | 1 Project MembersThe interactions between V. cholerae and macrophages are unclear, both in terms of the mechanisms and functions. By combining molecular techniques for the manipulation of V. cholerae and macrophages, as well as advanced transcriptome and imaging techniques, we will determine the molecular toolkits, mechanisms, and strategies that govern the interaction dynamics of V. cholerae and macrophages. This project will provide a foundational understanding of the infectious life cycle of V. cholerae within the host.
Zusammensetzung und Funktion von Vibrio cholerae Biofilmen auf humanen Makrophagen Research Project | 1 Project MembersCholera is a devastating diarrheal disease, caused by the bacterium Vibrio cholerae . Although V. cholerae induces an inflammatory response during infection, it is currently unclear how V. cholerae cells interact with the innate immune system. Focusing on the interaction of V. cholerae with macrophages, we discovered a surprising interaction process in preliminary work: V. cholerae cells form biofilms on the surface of macrophages, followed by macrophage death. In the proposed project, we will determine the key mechanisms underlying the formation, matrix composition, and function of biofilms on macrophages, and how macrophage death occurs during the interaction with V. cholerae . This project will provide a major new insight into the interaction mechanisms of V. cholerae with the human immune system.
BIOFAGE / Interaction Dynamics of Bacterial Biofilms with Bacteriophages Research Project | 1 Project MembersBiofilms are antibiotic-resistant, sessile bacterial communities that occupy most moist surfaces on Earth and represent a major mode of bacterial life. Another common feature of bacterial life is exposure to viral parasites (termed phages), which are a dominant force in bacterial population control throughout nature. Surprisingly, almost nothing is known about the interactions between biofilm-dwelling bacteria and phages. This proposal is designed to fill this gap using a combination of novel methodology, experimental systems, and mathematical modeling. We have recently developed a new microscopic imaging technique that allows us to image and track all individual cells and their gene expression inside biofilms. First, we will use this technique for tracking the population dynamics of bacteria and phages within biofilms at single cell resolution. By genetically manipulating bacterial hosts and their phages, and by varying environmental conditions, we will investigate the fundamental biological and physical determinants of phage spread within biofilm communities. Second, we will study how biofilms respond to phage attack on both intra-generational and evolutionary time scales, focusing in particular on proximate response mechanisms and the population dynamics of phage-resistant and phage-susceptible cells as a function of biofilm spatial structure. Lastly, we will combine our novel insights to engineer phages that manipulate the composition of biofilm communities, either by subtraction of particular bacterial species or by addition of novel phenotypes to existing biofilm community members. Altogether, the proposed research promises to uncover the major mechanistic and evolutionary elements of biofilm-phage interactions. This combined work will greatly enrich our knowledge of microbial ecology and motivate novel strategies for bacterial biofilm control, an increasingly urgent priority in light of widespread antibiotic resistance.
PHYMOT - Physics of Microbial Motility Research Project | 1 Project MembersSuspensions of swimming bacteria display collective motion when the density of bacteria increases. These collective movements take the form of large groups of cells that transiently move in the same direction, which break up into swirls, forming intermittent vortex-like structures. The cell-cell interaction mechanisms that underlie the emergence of bacterial collective motion in two- and three-dimensional suspensions are unclear. Using genetics, we will modify bacterial cells such that physical parameters of bacterial motility and bacterial cell surface-adhesiveness are altered, e.g. by changing the cellular aspect ratio, flagella length, flagellar rotation speed, and surface adhesion expression. These genetic modifications will alter key cellular properties that are predicted by theoretical models to change the bacterial cell-cell scattering interactions. These mutants will provide a basis for experimentally dissecting the contributions of different cellular properties to bacterial collective movement.
NCCR AntiResist: New approaches to combat antibiotic-resistant bacteria Umbrella Project | 32 Project MembersAntibiotics are powerful and indispensable drugs to treat life threatening bacterial infections such as sepsis or pneumonia. Antibiotics also play a central role in many other areas of modern medicine, in particular to protect patients with compromised immunity during cancer therapies, transplantations or surgical interventions. These achievements are now at risk, with the fraction of bacterial pathogens that are resistant to one or more antibiotics steadily increasing. In addition, development of novel antimicrobials lags behind, suffering from inherently high attrition rates in particular for drug candidates against the most problematic Gram-negative bacteria. Together, these factors increasingly limit the options clinicians have for treating bacterial infections. The overarching goal of NCCR AntiResist is to elucidate the physiological properties of bacterial pathogens in infected human patients in order to find new ways of combatting superbugs. Among the many societal, economic, and scientific factors that impact on the development of alternative strategies for antibiotic discovery, our limited understanding of the physiology and heterogeneity of bacterial pathogens in patients ranks highly. Bacteria growing in tissues of patients experience environments very different from standard laboratory conditions, resulting in radically different microbial physiology and population heterogeneity compared to conditions generally used for antibacterial discovery. There is currently no systematic strategy to overcome this fundamental problem. This has resulted in: (i) suboptimal screens that identify new antibiotics, which do not target the special properties of bacteria growing within the patient; (ii) an inability to properly evaluate the efficacy of non-conventional antibacterial strategies; (iii) missed opportunities for entirely new treatment strategies. This NCCR utilizes patient samples from ongoing clinical studies and establishes a unique multidisciplinary network of clinicians, biologists, engineers, chemists, computational scientists and drug developers that will overcome this problem. We are excited to merge these disciplines in order to determine the properties of pathogens infecting patients, establish conditions in the lab that reproduce these properties and utilize these in-vitro models for antimicrobial discovery and development. In addition, clinical-trial networks and the pharmaceutical industry have major footprints in antimicrobial R&D. Exploiting synergies between these players has great potential for making transformative progress in this critical field of human health. This NCCR maintains active collaborations with Biotech SMEs and large pharmaceutical companies with the goal to: accelerate antibiotic discovery by providing relevant read-outs for early prioritization of compounds; enable innovative screens for non-canonical strategies such as anti-virulence inhibitors and immunomodulators; identify new antibacterial strategies that effectively combat bacteria either by targeting refractory subpopulations or by synergizing with bacterial stresses imposed by the patients' own immune system. This NCCR proposes a paradigm shift in antibiotic discovery by investigating the physiology of bacterial pathogens in human patients. This knowledge will be used to develop assays for molecular analyses and drug screening under relevant conditions and to accelerate antibacterial discovery, improve treatment regimens, and uncover novel targets for eradicating pathogens. Through this concerted effort, this NCCR will make a crucial and unique contribution to winning the race against superbugs.
