Infection Biology (Basler)Head of Research Unit Prof. Dr.Marek BaslerOverviewMembersPublicationsProjects & CollaborationsProjects & Collaborations OverviewMembersPublicationsProjects & Collaborations Projects & Collaborations 11 foundShow per page10 10 20 50 Characterization of accessory proteins and signaling cascades involved in the regulation of the assembly of bacterial Type VI secretion systems Research Project | 1 Project MembersImported from Grants Tool 4701422 Decoding RNA packaging by analysis of single bacterial extracellular vesicles Research Project | 1 Project MembersImported from Grants Tool 4683330 The role of type VI secretion systems in infection and competition of intracellular pathogens (BIF Fellowship Hoi Ching Cheung) Research Project | 2 Project MembersThe Type VI Secretion System (T6SS) is a molecular machinery of Gram-negative bacteria which facilitates pathogenesis and interbacterial competition. Understanding the dynamics and function of T6SS is essential for therapeutic insights. Burkholderia is a Gram-negative bacterial genus with species such as B. pseudomallei and B. cenocepacia , which are the causative agents of high mortality diseases such as Melioidosis and Cystic Fibrosis-associated pneumonia in humans. Burkholderia contain one to six different T6SS. One of the systems, T6SS-5, can cause mammalian cells to form multinucleated giant cells (MNGC). These play an important role in virulence because they allow intracellular spread of bacteria. Moreover, Burkholderia uses T6SS-1 to outcompete other bacteria to persist in the host and the environment. In this project, molecular cloning, mammalian cell infection assays and bacterial competition assays, combined with confocal imaging and transcriptomic analysis, will be carried out to determine the dynamics and regulation of T6SS in phagocytic and non-phagocytic mammalian cells and during bacterial competitions. Furthermore, the role of host cell signals in T6SS regulation will be explored. This will provide insight on therapeutic targets for inhibiting the spread and attenuating virulence of Burkholderia infections. Home delivery: Bacterial sRNA mediated treatment of intestinal bowel disease (Freenovation Grant, Miro Plum and Maxim Kolesnikov) Research Project | 3 Project MembersInflammatory bowel disease is characterized by persistent inflammation of the colon and represents an increasing problem worldwide. Existing treatments are broad-acting, unspecific and are limited to temporary relief of symptoms. Moreover, the disease is highly heterogeneous, with a variety of possible causes that range from genetic to environmental. In our project, we will engineer a bacterium that secretes anti-inflammatory RNA in extracellular vesicles. Such a "living pill" may pave the way for further applications that involve RNA dependent regulation. A Death-Dealing Bacterial Nanomachine Research Project | 3 Project MembersType 6 secretion systems (T6SS) are harpoon-like nanomachines that Gram-negative bacterial cells employ to kill other bacterial and eukaryotic cells.Briefly, the T6SS weaponry is tethered to the bacterial cell envelope by a membrane complex, that serves as a platform upon which a baseplate, an extended spring-like sheath and a central spike are assembled. Sheath contraction is biochemically triggered and results in a rapid ejection of the central spike that pierces through a neighboring cell membrane to deliver toxins and other effectors into it. While fluorescence imaging and structural methods have provided deep insight into T6SS structure and function, its destructive mode of action remains unresolved. Here, we will use high-speed atomic force microscope (HS-AFM) imaging, as well as AFM indentation-type force spectroscopy and confocal microscopy (CM) to study the nanomechanical basis by which the T6SS spike punctures bacterial and eukaryotic cell membranes. Mechanisms of subcellular localization of the bacterial Type 6 secretion system assembly Research Project | 1 Project MembersNo Description available 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. Defining the molecular basis of dynamic localization of type VI secretion system assembly in Pseudomonas aeruginosa (BIF Fellowship Maxim Kolesnikov) Research Project | 2 Project MembersThe multifunctional type VI secretion system (T6SS) allows bacteria to deliver effectors to both eukaryotic and prokaryotic cells and thus to gain advantage during bacterial competition as well as pathogenesis. T6SS can be conceptualized as a speargun. Its mode of action is similar to contractile phage tails attached to the cytosolic side of the cell envelope. Upon contraction of T6SS sheath, a needle is protruded from the cell with great force. Knowledge of T6SS assembly regulation remains limited. The opportunistic pathogen Pseudomonas aeruginosa , which encodes three T6SS, targets both prokaryotic and eukaryotic cells by localizing T6SS assembly in response to membrane perturbation, believed to be sensed via a dedicated sensor module. Using P. aeruginosa as a model, the molecular mechanism of signaling in T6SS assembly will be determined by structural, biochemical and microscopy approaches. This work will provide fundamental insights into signaling mechanisms and T6SS assembly in an important human pathogen. EMBO Young Investigator Programme Award Research Project | 1 Project MembersMy lab studies structure, function and dynamics of the Type VI secretion system (T6SS). This nanomachine is evolutionarily related to contractile phage tails and delivers proteins into both bacterial and eukaryotic cells. We use various biochemical, genetic and imaging techniques to understand the key molecular mechanisms underlying the assembly, substrate delivery, and regulation of T6SS function during bacterial cell-cell interactions. Molecular mechanisms of force generation and protein translocation by contractile tails Research Project | 1 Project MembersThe fundamental problem of protein transport across biological membranes was solved by the evolution of sophisticated nanomachines that physically puncture the membranes by sharp cargo-loaded needles. These nanomachines are used by bacteria to deliver toxins into their competitors or host cells. Our project aims at mechanistic understanding of the nanomachine's mode of action. Type VI Secretion System (T6SS) is a poorly understood nanomachine that many Gram-negative bacteria use to kill both bacterial and eukaryotic cells. The main goal of this proposal is to address a fundamental question about T6SS: where does the force needed to secrete toxins into target cells come from? In frame of this proposal, we will use state-of-the-art electron microscopy techniques to obtain high resolution structures of diverse T6SS components from different organisms. We will test hypotheses about mechanisms of assembly by mutagenesis of T6SS components in model organisms and evaluation of the efficiency of substrate secretion and target cell killing. Overall, this project will provide a detailed understanding of how T6SS delivers proteins into target cells. Understanding of bacterial cell biology opens avenues for new approaches to inhibit bacterial pathogenesis. This proposal is aimed at one of the fundamental processes that bacteria use to influence their environment and thus has a potential to contribute to an ongoing effort to combat bacterial infections. 12 12 OverviewMembersPublicationsProjects & Collaborations
Projects & Collaborations 11 foundShow per page10 10 20 50 Characterization of accessory proteins and signaling cascades involved in the regulation of the assembly of bacterial Type VI secretion systems Research Project | 1 Project MembersImported from Grants Tool 4701422 Decoding RNA packaging by analysis of single bacterial extracellular vesicles Research Project | 1 Project MembersImported from Grants Tool 4683330 The role of type VI secretion systems in infection and competition of intracellular pathogens (BIF Fellowship Hoi Ching Cheung) Research Project | 2 Project MembersThe Type VI Secretion System (T6SS) is a molecular machinery of Gram-negative bacteria which facilitates pathogenesis and interbacterial competition. Understanding the dynamics and function of T6SS is essential for therapeutic insights. Burkholderia is a Gram-negative bacterial genus with species such as B. pseudomallei and B. cenocepacia , which are the causative agents of high mortality diseases such as Melioidosis and Cystic Fibrosis-associated pneumonia in humans. Burkholderia contain one to six different T6SS. One of the systems, T6SS-5, can cause mammalian cells to form multinucleated giant cells (MNGC). These play an important role in virulence because they allow intracellular spread of bacteria. Moreover, Burkholderia uses T6SS-1 to outcompete other bacteria to persist in the host and the environment. In this project, molecular cloning, mammalian cell infection assays and bacterial competition assays, combined with confocal imaging and transcriptomic analysis, will be carried out to determine the dynamics and regulation of T6SS in phagocytic and non-phagocytic mammalian cells and during bacterial competitions. Furthermore, the role of host cell signals in T6SS regulation will be explored. This will provide insight on therapeutic targets for inhibiting the spread and attenuating virulence of Burkholderia infections. Home delivery: Bacterial sRNA mediated treatment of intestinal bowel disease (Freenovation Grant, Miro Plum and Maxim Kolesnikov) Research Project | 3 Project MembersInflammatory bowel disease is characterized by persistent inflammation of the colon and represents an increasing problem worldwide. Existing treatments are broad-acting, unspecific and are limited to temporary relief of symptoms. Moreover, the disease is highly heterogeneous, with a variety of possible causes that range from genetic to environmental. In our project, we will engineer a bacterium that secretes anti-inflammatory RNA in extracellular vesicles. Such a "living pill" may pave the way for further applications that involve RNA dependent regulation. A Death-Dealing Bacterial Nanomachine Research Project | 3 Project MembersType 6 secretion systems (T6SS) are harpoon-like nanomachines that Gram-negative bacterial cells employ to kill other bacterial and eukaryotic cells.Briefly, the T6SS weaponry is tethered to the bacterial cell envelope by a membrane complex, that serves as a platform upon which a baseplate, an extended spring-like sheath and a central spike are assembled. Sheath contraction is biochemically triggered and results in a rapid ejection of the central spike that pierces through a neighboring cell membrane to deliver toxins and other effectors into it. While fluorescence imaging and structural methods have provided deep insight into T6SS structure and function, its destructive mode of action remains unresolved. Here, we will use high-speed atomic force microscope (HS-AFM) imaging, as well as AFM indentation-type force spectroscopy and confocal microscopy (CM) to study the nanomechanical basis by which the T6SS spike punctures bacterial and eukaryotic cell membranes. Mechanisms of subcellular localization of the bacterial Type 6 secretion system assembly Research Project | 1 Project MembersNo Description available 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. Defining the molecular basis of dynamic localization of type VI secretion system assembly in Pseudomonas aeruginosa (BIF Fellowship Maxim Kolesnikov) Research Project | 2 Project MembersThe multifunctional type VI secretion system (T6SS) allows bacteria to deliver effectors to both eukaryotic and prokaryotic cells and thus to gain advantage during bacterial competition as well as pathogenesis. T6SS can be conceptualized as a speargun. Its mode of action is similar to contractile phage tails attached to the cytosolic side of the cell envelope. Upon contraction of T6SS sheath, a needle is protruded from the cell with great force. Knowledge of T6SS assembly regulation remains limited. The opportunistic pathogen Pseudomonas aeruginosa , which encodes three T6SS, targets both prokaryotic and eukaryotic cells by localizing T6SS assembly in response to membrane perturbation, believed to be sensed via a dedicated sensor module. Using P. aeruginosa as a model, the molecular mechanism of signaling in T6SS assembly will be determined by structural, biochemical and microscopy approaches. This work will provide fundamental insights into signaling mechanisms and T6SS assembly in an important human pathogen. EMBO Young Investigator Programme Award Research Project | 1 Project MembersMy lab studies structure, function and dynamics of the Type VI secretion system (T6SS). This nanomachine is evolutionarily related to contractile phage tails and delivers proteins into both bacterial and eukaryotic cells. We use various biochemical, genetic and imaging techniques to understand the key molecular mechanisms underlying the assembly, substrate delivery, and regulation of T6SS function during bacterial cell-cell interactions. Molecular mechanisms of force generation and protein translocation by contractile tails Research Project | 1 Project MembersThe fundamental problem of protein transport across biological membranes was solved by the evolution of sophisticated nanomachines that physically puncture the membranes by sharp cargo-loaded needles. These nanomachines are used by bacteria to deliver toxins into their competitors or host cells. Our project aims at mechanistic understanding of the nanomachine's mode of action. Type VI Secretion System (T6SS) is a poorly understood nanomachine that many Gram-negative bacteria use to kill both bacterial and eukaryotic cells. The main goal of this proposal is to address a fundamental question about T6SS: where does the force needed to secrete toxins into target cells come from? In frame of this proposal, we will use state-of-the-art electron microscopy techniques to obtain high resolution structures of diverse T6SS components from different organisms. We will test hypotheses about mechanisms of assembly by mutagenesis of T6SS components in model organisms and evaluation of the efficiency of substrate secretion and target cell killing. Overall, this project will provide a detailed understanding of how T6SS delivers proteins into target cells. Understanding of bacterial cell biology opens avenues for new approaches to inhibit bacterial pathogenesis. This proposal is aimed at one of the fundamental processes that bacteria use to influence their environment and thus has a potential to contribute to an ongoing effort to combat bacterial infections. 12 12
Characterization of accessory proteins and signaling cascades involved in the regulation of the assembly of bacterial Type VI secretion systems Research Project | 1 Project MembersImported from Grants Tool 4701422
Decoding RNA packaging by analysis of single bacterial extracellular vesicles Research Project | 1 Project MembersImported from Grants Tool 4683330
The role of type VI secretion systems in infection and competition of intracellular pathogens (BIF Fellowship Hoi Ching Cheung) Research Project | 2 Project MembersThe Type VI Secretion System (T6SS) is a molecular machinery of Gram-negative bacteria which facilitates pathogenesis and interbacterial competition. Understanding the dynamics and function of T6SS is essential for therapeutic insights. Burkholderia is a Gram-negative bacterial genus with species such as B. pseudomallei and B. cenocepacia , which are the causative agents of high mortality diseases such as Melioidosis and Cystic Fibrosis-associated pneumonia in humans. Burkholderia contain one to six different T6SS. One of the systems, T6SS-5, can cause mammalian cells to form multinucleated giant cells (MNGC). These play an important role in virulence because they allow intracellular spread of bacteria. Moreover, Burkholderia uses T6SS-1 to outcompete other bacteria to persist in the host and the environment. In this project, molecular cloning, mammalian cell infection assays and bacterial competition assays, combined with confocal imaging and transcriptomic analysis, will be carried out to determine the dynamics and regulation of T6SS in phagocytic and non-phagocytic mammalian cells and during bacterial competitions. Furthermore, the role of host cell signals in T6SS regulation will be explored. This will provide insight on therapeutic targets for inhibiting the spread and attenuating virulence of Burkholderia infections.
Home delivery: Bacterial sRNA mediated treatment of intestinal bowel disease (Freenovation Grant, Miro Plum and Maxim Kolesnikov) Research Project | 3 Project MembersInflammatory bowel disease is characterized by persistent inflammation of the colon and represents an increasing problem worldwide. Existing treatments are broad-acting, unspecific and are limited to temporary relief of symptoms. Moreover, the disease is highly heterogeneous, with a variety of possible causes that range from genetic to environmental. In our project, we will engineer a bacterium that secretes anti-inflammatory RNA in extracellular vesicles. Such a "living pill" may pave the way for further applications that involve RNA dependent regulation.
A Death-Dealing Bacterial Nanomachine Research Project | 3 Project MembersType 6 secretion systems (T6SS) are harpoon-like nanomachines that Gram-negative bacterial cells employ to kill other bacterial and eukaryotic cells.Briefly, the T6SS weaponry is tethered to the bacterial cell envelope by a membrane complex, that serves as a platform upon which a baseplate, an extended spring-like sheath and a central spike are assembled. Sheath contraction is biochemically triggered and results in a rapid ejection of the central spike that pierces through a neighboring cell membrane to deliver toxins and other effectors into it. While fluorescence imaging and structural methods have provided deep insight into T6SS structure and function, its destructive mode of action remains unresolved. Here, we will use high-speed atomic force microscope (HS-AFM) imaging, as well as AFM indentation-type force spectroscopy and confocal microscopy (CM) to study the nanomechanical basis by which the T6SS spike punctures bacterial and eukaryotic cell membranes.
Mechanisms of subcellular localization of the bacterial Type 6 secretion system assembly Research Project | 1 Project MembersNo Description available
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.
Defining the molecular basis of dynamic localization of type VI secretion system assembly in Pseudomonas aeruginosa (BIF Fellowship Maxim Kolesnikov) Research Project | 2 Project MembersThe multifunctional type VI secretion system (T6SS) allows bacteria to deliver effectors to both eukaryotic and prokaryotic cells and thus to gain advantage during bacterial competition as well as pathogenesis. T6SS can be conceptualized as a speargun. Its mode of action is similar to contractile phage tails attached to the cytosolic side of the cell envelope. Upon contraction of T6SS sheath, a needle is protruded from the cell with great force. Knowledge of T6SS assembly regulation remains limited. The opportunistic pathogen Pseudomonas aeruginosa , which encodes three T6SS, targets both prokaryotic and eukaryotic cells by localizing T6SS assembly in response to membrane perturbation, believed to be sensed via a dedicated sensor module. Using P. aeruginosa as a model, the molecular mechanism of signaling in T6SS assembly will be determined by structural, biochemical and microscopy approaches. This work will provide fundamental insights into signaling mechanisms and T6SS assembly in an important human pathogen.
EMBO Young Investigator Programme Award Research Project | 1 Project MembersMy lab studies structure, function and dynamics of the Type VI secretion system (T6SS). This nanomachine is evolutionarily related to contractile phage tails and delivers proteins into both bacterial and eukaryotic cells. We use various biochemical, genetic and imaging techniques to understand the key molecular mechanisms underlying the assembly, substrate delivery, and regulation of T6SS function during bacterial cell-cell interactions.
Molecular mechanisms of force generation and protein translocation by contractile tails Research Project | 1 Project MembersThe fundamental problem of protein transport across biological membranes was solved by the evolution of sophisticated nanomachines that physically puncture the membranes by sharp cargo-loaded needles. These nanomachines are used by bacteria to deliver toxins into their competitors or host cells. Our project aims at mechanistic understanding of the nanomachine's mode of action. Type VI Secretion System (T6SS) is a poorly understood nanomachine that many Gram-negative bacteria use to kill both bacterial and eukaryotic cells. The main goal of this proposal is to address a fundamental question about T6SS: where does the force needed to secrete toxins into target cells come from? In frame of this proposal, we will use state-of-the-art electron microscopy techniques to obtain high resolution structures of diverse T6SS components from different organisms. We will test hypotheses about mechanisms of assembly by mutagenesis of T6SS components in model organisms and evaluation of the efficiency of substrate secretion and target cell killing. Overall, this project will provide a detailed understanding of how T6SS delivers proteins into target cells. Understanding of bacterial cell biology opens avenues for new approaches to inhibit bacterial pathogenesis. This proposal is aimed at one of the fundamental processes that bacteria use to influence their environment and thus has a potential to contribute to an ongoing effort to combat bacterial infections.
