Project acronym AsthmaVir
Project The roles of innate lymphoid cells and rhinovirus in asthma exacerbations
Researcher (PI) Hergen Spits
Host Institution (HI) Academisch Medisch Centrum bij de Universiteit van Amsterdam
Call Details Advanced Grant (AdG), LS6, ERC-2013-ADG
Summary Asthma exacerbations represent a high unmet medical need in particular in young children. Human Rhinoviruses (HRV) are the main triggers of these exacerbations. Till now Th2 cells were considered the main initiating effector cell type in asthma in general and asthma exacerbations in particular. However, exaggerated Th2 cell activities alone do not explain all aspects of asthma and exacerbations. Building on our recent discovery of type 2 human innate lymphoid cells (ILC2) capable of promptly producing high amounts of IL-5, IL-9 and IL-13 upon activation and on mouse data pointing to an essential role of these cells in asthma and asthma exacerbations, ILC2 may be the main initiating cells in asthma exacerbations in humans. Thus we hypothesize that HRV directly or indirectly stimulate ILC2s to produce cytokines driving the effector functions leading to the end organ effects that characterize this debilitating disease. Targeting ILC2 and HRV in parallel will provide a highly attractive therapeutic option for the treatment of asthma exacerbations. In depth study of the mechanisms of ILC2 differentiation and function will lead to the design effective drugs targeting these cells; thus the first two objectives of this project are: 1) To unravel the lineage relationship of ILC populations and to decipher the signal transduction pathways that regulate the function of ILCs, 2) to test the functions of lung-residing human ILCs and the effects of compounds that affect these functions in mice which harbour a human immune system and human lung epithelium under homeostatic conditions and after infections with respiratory viruses. The third objective of this project is developing reagents that target HRV; to this end we will develop broadly reacting highly neutralizing human monoclonal antibodies that can be used for prophylaxis and therapy of patients at high risk for developing severe asthma exacerbations.
Summary
Asthma exacerbations represent a high unmet medical need in particular in young children. Human Rhinoviruses (HRV) are the main triggers of these exacerbations. Till now Th2 cells were considered the main initiating effector cell type in asthma in general and asthma exacerbations in particular. However, exaggerated Th2 cell activities alone do not explain all aspects of asthma and exacerbations. Building on our recent discovery of type 2 human innate lymphoid cells (ILC2) capable of promptly producing high amounts of IL-5, IL-9 and IL-13 upon activation and on mouse data pointing to an essential role of these cells in asthma and asthma exacerbations, ILC2 may be the main initiating cells in asthma exacerbations in humans. Thus we hypothesize that HRV directly or indirectly stimulate ILC2s to produce cytokines driving the effector functions leading to the end organ effects that characterize this debilitating disease. Targeting ILC2 and HRV in parallel will provide a highly attractive therapeutic option for the treatment of asthma exacerbations. In depth study of the mechanisms of ILC2 differentiation and function will lead to the design effective drugs targeting these cells; thus the first two objectives of this project are: 1) To unravel the lineage relationship of ILC populations and to decipher the signal transduction pathways that regulate the function of ILCs, 2) to test the functions of lung-residing human ILCs and the effects of compounds that affect these functions in mice which harbour a human immune system and human lung epithelium under homeostatic conditions and after infections with respiratory viruses. The third objective of this project is developing reagents that target HRV; to this end we will develop broadly reacting highly neutralizing human monoclonal antibodies that can be used for prophylaxis and therapy of patients at high risk for developing severe asthma exacerbations.
Max ERC Funding
2 499 593 €
Duration
Start date: 2014-03-01, End date: 2019-02-28
Project acronym Autonomous CLL-BCRs
Project Role of autonomous B cell receptor signalling and external antigen in the pathogenesis of chronic lymphocytic leukaemia (CLL)
Researcher (PI) Hassan JUMAA-WEINACHT
Host Institution (HI) UNIVERSITAET ULM
Call Details Advanced Grant (AdG), LS6, ERC-2015-AdG
Summary The proposed project aims at investigating the molecular mechanisms that activate B cell antigen receptor (BCR) signalling in chronic lymphocytic leukaemia (CLL). While it is widely accepted that the unbroken BCR expression in CLL cells is indicative for a key role in disease development, the mechanisms that induce BCR activation and survival of malignant cells are still elusive. Using a unique reconstitution system, we have recently shown that CLL-derived BCRs possess the exceptional capacity for cell-autonomous signalling independent of external antigen. Crystallographic analyses confirmed our model that CLL-BCRs bind to intrinsic motifs in nearby BCRs on the very same cell. In addition to the BCR, several pathogenic factors influence the biological behaviour of CLL cells, but the functional hierarchy and the effect on BCR signalling are insufficiently understood. Here, we aim at investigating the structural cause of autonomous signalling as well as the characterization of important signalling pathways and their mechanistic action in CLL pathogenesis.
By combining crystallography with the measurement of autonomous signalling of wild type and mutated receptors in our unique reconstitution system, we will generate a structure-function relationship for CLL-BCRs. By generating new animal models and by employing classical as well as cutting-edge approaches of biochemistry and molecular/cellular immunology, we will comprehensively characterize the signalling pathways that are activated by autonomous signalling and might be important for CLL pathogenesis.
These systematic efforts are necessary to understand how various biological mechanisms operate and ultimately activate downstream pathways that result in a lymphoproliferative disease. In addition, a cohesive model of CLL pathogenesis, which elucidates the hierarchical order of pathogenic factors and their interaction with BCR signalling, may well lead to novel disease-specific preventive or therapeutic intervention.
Summary
The proposed project aims at investigating the molecular mechanisms that activate B cell antigen receptor (BCR) signalling in chronic lymphocytic leukaemia (CLL). While it is widely accepted that the unbroken BCR expression in CLL cells is indicative for a key role in disease development, the mechanisms that induce BCR activation and survival of malignant cells are still elusive. Using a unique reconstitution system, we have recently shown that CLL-derived BCRs possess the exceptional capacity for cell-autonomous signalling independent of external antigen. Crystallographic analyses confirmed our model that CLL-BCRs bind to intrinsic motifs in nearby BCRs on the very same cell. In addition to the BCR, several pathogenic factors influence the biological behaviour of CLL cells, but the functional hierarchy and the effect on BCR signalling are insufficiently understood. Here, we aim at investigating the structural cause of autonomous signalling as well as the characterization of important signalling pathways and their mechanistic action in CLL pathogenesis.
By combining crystallography with the measurement of autonomous signalling of wild type and mutated receptors in our unique reconstitution system, we will generate a structure-function relationship for CLL-BCRs. By generating new animal models and by employing classical as well as cutting-edge approaches of biochemistry and molecular/cellular immunology, we will comprehensively characterize the signalling pathways that are activated by autonomous signalling and might be important for CLL pathogenesis.
These systematic efforts are necessary to understand how various biological mechanisms operate and ultimately activate downstream pathways that result in a lymphoproliferative disease. In addition, a cohesive model of CLL pathogenesis, which elucidates the hierarchical order of pathogenic factors and their interaction with BCR signalling, may well lead to novel disease-specific preventive or therapeutic intervention.
Max ERC Funding
2 256 250 €
Duration
Start date: 2016-11-01, End date: 2021-10-31
Project acronym B-response
Project Memory and innate-like B-cell subsets: deciphering a multi-layered B-cell response in mice and humans
Researcher (PI) Claude-Agnes REYNAUD
Host Institution (HI) INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
Call Details Advanced Grant (AdG), LS6, ERC-2015-AdG
Summary B cells are the main actors of successful vaccines, and their protective capacity relies on several subsets with innate-like and memory properties that fulfill different effector functions. In the present project, we wish to develop approaches in both mice and humans, to confront the similarities and the differences of their B cell responses.
The three aims proposed are:
1) To study the different B cell subsets and TFH cells engaged in a memory response through the use of a new mouse reporter line allowing their irreversible labeling (inducible Cre recombinase under the control of the Bcl6 gene): this will be performed in different conditions of TH1 vs. TH2 polarization, as well as during a chronic viral infection, in which virus-specific antibodies have been shown to be required to control the disease (in collaboration with D. Pinschewer, Basel)
2) To study whether the lifelong persistence of B cell memory, as occurs for memory B cells against smallpox that we can obtain at high purity from aged donor's spleens, corresponds to a specific transcriptional program at the miRNA, lncRNA or mRNA level, as well as a specific cell homeostasis
3) To discriminate the specific effector function of human marginal zone and IgM memory B cells in, respectively, T-independent and T-dependent responses, as well as their specific differentiation/diversification pathway.
The general goal is to delineate the regulatory pathways leading to the activation and persistence of the different B cell subsets, allowing for a better understanding of the conditions leading to their pathological or beneficial mobilization.
Summary
B cells are the main actors of successful vaccines, and their protective capacity relies on several subsets with innate-like and memory properties that fulfill different effector functions. In the present project, we wish to develop approaches in both mice and humans, to confront the similarities and the differences of their B cell responses.
The three aims proposed are:
1) To study the different B cell subsets and TFH cells engaged in a memory response through the use of a new mouse reporter line allowing their irreversible labeling (inducible Cre recombinase under the control of the Bcl6 gene): this will be performed in different conditions of TH1 vs. TH2 polarization, as well as during a chronic viral infection, in which virus-specific antibodies have been shown to be required to control the disease (in collaboration with D. Pinschewer, Basel)
2) To study whether the lifelong persistence of B cell memory, as occurs for memory B cells against smallpox that we can obtain at high purity from aged donor's spleens, corresponds to a specific transcriptional program at the miRNA, lncRNA or mRNA level, as well as a specific cell homeostasis
3) To discriminate the specific effector function of human marginal zone and IgM memory B cells in, respectively, T-independent and T-dependent responses, as well as their specific differentiation/diversification pathway.
The general goal is to delineate the regulatory pathways leading to the activation and persistence of the different B cell subsets, allowing for a better understanding of the conditions leading to their pathological or beneficial mobilization.
Max ERC Funding
2 098 750 €
Duration
Start date: 2016-09-01, End date: 2021-08-31
Project acronym BacRafts
Project Architecture of bacterial lipid rafts; inhibition of virulence and antibiotic resistance using raft-disassembling small molecules
Researcher (PI) Daniel López Serrano
Host Institution (HI) AGENCIA ESTATAL CONSEJO SUPERIOR DE INVESTIGACIONES CIENTIFICAS
Call Details Starting Grant (StG), LS6, ERC-2013-StG
Summary Membranes of eukaryotic cells organize signal transduction proteins into microdomains or lipid rafts whose integrity is essential for numerous cellular processes. Lipid rafts has been considered a fundamental step to define the cellular complexity of eukaryotes, assuming that bacteria do not require such a sophisticated organization of their signaling networks. However, I have discovered that bacteria organize many signaling pathways in membrane microdomains similar to the eukaryotic lipid rafts. Perturbation of bacterial lipid rafts leads to a potent and simultaneous impairment of all raft-harbored signaling pathways. Consequently, the disassembly of lipid rafts in pathogens like Staphylococcus aureus generates a simultaneous inhibition of numerous infection-related processes that can be further explored to control bacterial infections. This unexpected sophistication in membrane organization is unprecedented in bacteria and hence, this proposal will explore the molecular basis of the assembly of bacterial lipid rafts and their role in the infection-related processes. These questions will be addressed in three main goals: First, I will elucidate the molecular components and the mechanism of assembly of bacterial lipid rafts using S. aureus as model organism. Second, I will dissect the molecular basis that links the functionality of the infection-related processes to the integrity of bacterial lipid rafts. Third, my collection of anti-raft small molecules that are able to disrupt lipid rafts will be tested as antimicrobial agents to prevent hospital-acquired infections, abrogate pre-existing infections and develop bacteria-free materials that can be used in clinical settings. I will use a number of molecular approaches in combination with cutting-edge techniques in flow cytometry, cell-imaging and transcriptomics to clarify the architecture and functionality of lipid rafts and demonstrate the feasibility of targeting lipid a new strategy for anti-microbial therapy.
Summary
Membranes of eukaryotic cells organize signal transduction proteins into microdomains or lipid rafts whose integrity is essential for numerous cellular processes. Lipid rafts has been considered a fundamental step to define the cellular complexity of eukaryotes, assuming that bacteria do not require such a sophisticated organization of their signaling networks. However, I have discovered that bacteria organize many signaling pathways in membrane microdomains similar to the eukaryotic lipid rafts. Perturbation of bacterial lipid rafts leads to a potent and simultaneous impairment of all raft-harbored signaling pathways. Consequently, the disassembly of lipid rafts in pathogens like Staphylococcus aureus generates a simultaneous inhibition of numerous infection-related processes that can be further explored to control bacterial infections. This unexpected sophistication in membrane organization is unprecedented in bacteria and hence, this proposal will explore the molecular basis of the assembly of bacterial lipid rafts and their role in the infection-related processes. These questions will be addressed in three main goals: First, I will elucidate the molecular components and the mechanism of assembly of bacterial lipid rafts using S. aureus as model organism. Second, I will dissect the molecular basis that links the functionality of the infection-related processes to the integrity of bacterial lipid rafts. Third, my collection of anti-raft small molecules that are able to disrupt lipid rafts will be tested as antimicrobial agents to prevent hospital-acquired infections, abrogate pre-existing infections and develop bacteria-free materials that can be used in clinical settings. I will use a number of molecular approaches in combination with cutting-edge techniques in flow cytometry, cell-imaging and transcriptomics to clarify the architecture and functionality of lipid rafts and demonstrate the feasibility of targeting lipid a new strategy for anti-microbial therapy.
Max ERC Funding
1 493 126 €
Duration
Start date: 2014-03-01, End date: 2019-02-28
Project acronym BACTERIAL RESPONSE
Project New Concepts in Bacterial Response to their Surroundings
Researcher (PI) Sigal Ben-Yehuda
Host Institution (HI) THE HEBREW UNIVERSITY OF JERUSALEM
Call Details Advanced Grant (AdG), LS6, ERC-2013-ADG
Summary Bacteria in nature exhibit remarkable capacity to sense their surroundings and rapidly adapt to diverse conditions by gaining new beneficial traits. This extraordinary feature facilitates their survival when facing extreme environments. Utilizing Bacillus subtilis as our primary model organism, we propose to study two facets of this vital bacterial attribute: communication via extracellular nanotubes, and persistence as resilient spores while maintaining the potential to revive. Exploring these fascinating aspects of bacterial physiology is likely to change our view as to how bacteria sense, respond, endure and communicate with their extracellular environment.
We have recently discovered a previously uncharacterized mode of bacterial communication, mediated by tubular extensions (nanotubes) that bridge neighboring cells, providing a route for exchange of intracellular molecules. Nanotube-mediated molecular sharing may represent a key form of bacterial communication in nature, allowing for the emergence of new phenotypes and increasing survival in fluctuating environments. Here we propose to develop strategies for observing nanotube formation and molecular exchange in living bacterial cells, and to characterize the molecular composition of nanotubes. We will explore the premise that nanotubes serve as a strategy to expand the cell surface, and will determine whether nanotubes provide a conduit for phage infection and spreading. Furthermore, the formation and functionality of interspecies nanotubes will be explored. An additional mode employed by bacteria to achieve extreme robustness is the ability to reside as long lasting spores. Previously held views considered the spore to be dormant and metabolically inert. However, we have recently shown that at least one week following spore formation, during an adaptive period, the spore senses and responds to environmental cues and undergoes corresponding molecular changes, influencing subsequent emergence from quiescence.
Summary
Bacteria in nature exhibit remarkable capacity to sense their surroundings and rapidly adapt to diverse conditions by gaining new beneficial traits. This extraordinary feature facilitates their survival when facing extreme environments. Utilizing Bacillus subtilis as our primary model organism, we propose to study two facets of this vital bacterial attribute: communication via extracellular nanotubes, and persistence as resilient spores while maintaining the potential to revive. Exploring these fascinating aspects of bacterial physiology is likely to change our view as to how bacteria sense, respond, endure and communicate with their extracellular environment.
We have recently discovered a previously uncharacterized mode of bacterial communication, mediated by tubular extensions (nanotubes) that bridge neighboring cells, providing a route for exchange of intracellular molecules. Nanotube-mediated molecular sharing may represent a key form of bacterial communication in nature, allowing for the emergence of new phenotypes and increasing survival in fluctuating environments. Here we propose to develop strategies for observing nanotube formation and molecular exchange in living bacterial cells, and to characterize the molecular composition of nanotubes. We will explore the premise that nanotubes serve as a strategy to expand the cell surface, and will determine whether nanotubes provide a conduit for phage infection and spreading. Furthermore, the formation and functionality of interspecies nanotubes will be explored. An additional mode employed by bacteria to achieve extreme robustness is the ability to reside as long lasting spores. Previously held views considered the spore to be dormant and metabolically inert. However, we have recently shown that at least one week following spore formation, during an adaptive period, the spore senses and responds to environmental cues and undergoes corresponding molecular changes, influencing subsequent emergence from quiescence.
Max ERC Funding
1 497 800 €
Duration
Start date: 2014-04-01, End date: 2019-03-31
Project acronym BoneMalar
Project Mechanisms of bone marrow sequestration during malaria infection
Researcher (PI) Matthias Marti
Host Institution (HI) UNIVERSITY OF GLASGOW
Call Details Consolidator Grant (CoG), LS6, ERC-2015-CoG
Summary Malaria remains a major problem of public health in developing countries. It is responsible for about 600000 deaths per year, predominantly children in sub-Saharan Africa. There is an urgent need for novel therapies as resistance against current treatments is widespread. The complex parasite biology requires a multifaceted approach targeting multiple life cycle stages and virulence pathways. The pathogenesis of the most deadly of human malaria parasites, Plasmodium falciparum, is related to the capability of infected red blood cells to sequester in deep tissues. Sequestration is critical for the completion of the red blood cell cycle because the release of parasites into the blood circulation allows recognition by surveillance macrophages and clearance in the spleen. A series of studies have since led to the understanding that sequestration of asexually replicating parasites is caused by the adherence of parasite infected red blood cells to the vascular endothelium of various tissues in the body.
We have recently demonstrated that gametocytes, the only stage capable of transmission to the mosquito vector, develop in the extravascular environment of the human bone marrow. Preliminary studies in the mouse model have confirmed this finding and also suggest existence of an asexual reservoir in the bone marrow. In this innovative multidiscipinary proposal we aim to investigate the host pathogen interactions at the interface between infected red blood cell and bone marrow vasculature. Specifically we will focus on the following questions: how do parasites home to bone marrow? What are the changes in the bone marrow endothelium upon infection? How do parasites adhere with and transmigrate across the vascular endothelium in the bone marrow? The proposed studies initiate detailed characterization of a new paradigm in malaria parasite interaction with the host vasculature and provide a compelling new avenue for intervention strategies.
Summary
Malaria remains a major problem of public health in developing countries. It is responsible for about 600000 deaths per year, predominantly children in sub-Saharan Africa. There is an urgent need for novel therapies as resistance against current treatments is widespread. The complex parasite biology requires a multifaceted approach targeting multiple life cycle stages and virulence pathways. The pathogenesis of the most deadly of human malaria parasites, Plasmodium falciparum, is related to the capability of infected red blood cells to sequester in deep tissues. Sequestration is critical for the completion of the red blood cell cycle because the release of parasites into the blood circulation allows recognition by surveillance macrophages and clearance in the spleen. A series of studies have since led to the understanding that sequestration of asexually replicating parasites is caused by the adherence of parasite infected red blood cells to the vascular endothelium of various tissues in the body.
We have recently demonstrated that gametocytes, the only stage capable of transmission to the mosquito vector, develop in the extravascular environment of the human bone marrow. Preliminary studies in the mouse model have confirmed this finding and also suggest existence of an asexual reservoir in the bone marrow. In this innovative multidiscipinary proposal we aim to investigate the host pathogen interactions at the interface between infected red blood cell and bone marrow vasculature. Specifically we will focus on the following questions: how do parasites home to bone marrow? What are the changes in the bone marrow endothelium upon infection? How do parasites adhere with and transmigrate across the vascular endothelium in the bone marrow? The proposed studies initiate detailed characterization of a new paradigm in malaria parasite interaction with the host vasculature and provide a compelling new avenue for intervention strategies.
Max ERC Funding
2 298 557 €
Duration
Start date: 2016-06-01, End date: 2021-05-31
Project acronym Born-Immune
Project Shaping of the Human Immune System by Primal Environmental Exposures In the Newborn Child
Researcher (PI) Klas Erik Petter Brodin
Host Institution (HI) KAROLINSKA INSTITUTET
Call Details Starting Grant (StG), LS6, ERC-2015-STG
Summary Immune systems are highly variable, but the sources of this variation are poorly understood. Genetic variation only explains a minor fraction of this, and we are unable to accurately predict the risk of immune mediated disease or severe infection in any given individual. I recently found that immune cells and proteins in healthy twins vary because of non-heritable influences (infections, vaccines, microbiota etc.), with only minor influences from heritable factors (Brodin, et al, Cell 2015). When and how such environmental influences shape our immune system is now important to understand. Birth represents the most transformational change in environment during the life of any individual. I propose, that environmental influences at birth, and during the first months of life could be particularly influential by imprinting on the regulatory mechanisms forming in the developing immune system. Adaptive changes in immune cell frequencies and functional states induced by early-life exposures could determine both the immune competence of the newborn, but potentially also its long-term trajectory towards immunological health or disease. Here, I propose a study of 1000 newborn children, followed longitudinally during their first 1000 days of life. By monitoring immune profiles and recording many environmental influences, we hope to understand how early life exposures can influence human immune system development. We have established a new assay based on Mass Cytometry and necessary data analysis tools (Brodin, et al, PNAS 2014), to simultaneously monitor the frequencies, phenotypes and functional states of more than 200 blood immune cell populations from only 100 microliters of blood. By monitoring environmental influences at regular follow-up visits, by questionnaires, serum measurements of infection, and gut microbiome sequencing, we aim to provide the most comprehensive analysis to date of immune system development in newborn children.
Summary
Immune systems are highly variable, but the sources of this variation are poorly understood. Genetic variation only explains a minor fraction of this, and we are unable to accurately predict the risk of immune mediated disease or severe infection in any given individual. I recently found that immune cells and proteins in healthy twins vary because of non-heritable influences (infections, vaccines, microbiota etc.), with only minor influences from heritable factors (Brodin, et al, Cell 2015). When and how such environmental influences shape our immune system is now important to understand. Birth represents the most transformational change in environment during the life of any individual. I propose, that environmental influences at birth, and during the first months of life could be particularly influential by imprinting on the regulatory mechanisms forming in the developing immune system. Adaptive changes in immune cell frequencies and functional states induced by early-life exposures could determine both the immune competence of the newborn, but potentially also its long-term trajectory towards immunological health or disease. Here, I propose a study of 1000 newborn children, followed longitudinally during their first 1000 days of life. By monitoring immune profiles and recording many environmental influences, we hope to understand how early life exposures can influence human immune system development. We have established a new assay based on Mass Cytometry and necessary data analysis tools (Brodin, et al, PNAS 2014), to simultaneously monitor the frequencies, phenotypes and functional states of more than 200 blood immune cell populations from only 100 microliters of blood. By monitoring environmental influences at regular follow-up visits, by questionnaires, serum measurements of infection, and gut microbiome sequencing, we aim to provide the most comprehensive analysis to date of immune system development in newborn children.
Max ERC Funding
1 422 339 €
Duration
Start date: 2016-07-01, End date: 2021-06-30
Project acronym CD4DNASP
Project Cell intrinsic control of CD4 T cell differentiation by cytosolic DNA sensing pathways
Researcher (PI) Lionel Jerome Apetoh
Host Institution (HI) INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
Call Details Starting Grant (StG), LS6, ERC-2015-STG
Summary This proposal aims to investigate the role of cytosolic DNA sensing pathways in CD4 T cell differentiation.
Cellular host defense to pathogens relies on the detection of pathogen-associated molecular patterns including deoxyribonucleic acid (DNA), which can be recognized by host myeloid cells through Toll-like receptor (TLR) 9 binding. Recent evidence however suggests that innate immune cells can also perceive cytoplasmic DNA from infectious or autologous origin through cytosolic DNA sensors triggering TLR9-independent signaling. Activation of cytosolic DNA sensor-dependent signaling pathways has been clearly shown to trigger innate immune responses to microbial and host DNA, but the contribution of cytosolic DNA sensors to the differentiation of CD4 T cells, an essential event for shaping adaptive immune responses, has not been documented. This proposal aims to fill this current knowledge gap.
We aim to decipher the molecular series of transcriptional events triggered by DNA in CD4 T cells that ultimately result in altered T cell differentiation. This aim will be addressed by combining in vitro and in vivo approaches such as advanced gene expression analysis of CD4 T cells and use of transgenic and gene-deficient mice. Structure activity relationship and biophysical studies will also be performed to unravel novel immunomodulators able to affect CD4 T cell differentiation.
Summary
This proposal aims to investigate the role of cytosolic DNA sensing pathways in CD4 T cell differentiation.
Cellular host defense to pathogens relies on the detection of pathogen-associated molecular patterns including deoxyribonucleic acid (DNA), which can be recognized by host myeloid cells through Toll-like receptor (TLR) 9 binding. Recent evidence however suggests that innate immune cells can also perceive cytoplasmic DNA from infectious or autologous origin through cytosolic DNA sensors triggering TLR9-independent signaling. Activation of cytosolic DNA sensor-dependent signaling pathways has been clearly shown to trigger innate immune responses to microbial and host DNA, but the contribution of cytosolic DNA sensors to the differentiation of CD4 T cells, an essential event for shaping adaptive immune responses, has not been documented. This proposal aims to fill this current knowledge gap.
We aim to decipher the molecular series of transcriptional events triggered by DNA in CD4 T cells that ultimately result in altered T cell differentiation. This aim will be addressed by combining in vitro and in vivo approaches such as advanced gene expression analysis of CD4 T cells and use of transgenic and gene-deficient mice. Structure activity relationship and biophysical studies will also be performed to unravel novel immunomodulators able to affect CD4 T cell differentiation.
Max ERC Funding
1 500 000 €
Duration
Start date: 2016-08-01, End date: 2021-07-31
Project acronym CMIL
Project Crosstalk of Metabolism and Inflammation
Researcher (PI) Andreas Bergthaler
Host Institution (HI) CEMM - FORSCHUNGSZENTRUM FUER MOLEKULARE MEDIZIN GMBH
Call Details Starting Grant (StG), LS6, ERC-2015-STG
Summary Inflammation is a response to noxious stimuli and initiates tissue repair. If resolution fails, however, chronic inflammation develops, which drives tissue damage in many diseases including autoimmunity, cancer and infections. Inflammatory processes are increasingly being appreciated as tightly integrated with metabolic pathways. The molecular crosstalk occurs on different levels including secreted metabolites and cytokines. I hypothesise that this interface of metabolism and inflammation represents a functional rheostat that shapes tissue damage and disease.
Here, I propose to analyse the metabolic and inflammatory processes in a mouse model of chronic viral hepatitis. I chose this model to explore the inflammatory rheostat because the liver is the central organ for metabolism and a hotspot for receiving, processing and distributing local and systemic signals. Cutting-edge technologies including deep sequencing, quantitative proteomics and metabolomics will let us create longitudinal multi-dimensional maps of virus-induced alterations. Paired with immunological, virological and pathological analyses, I expect to identify novel regulatory nodes between metabolism and inflammation. Within our systems-wide experiments and supported by preliminary results, we will specifically focus on the immunomodulatory roles of the metabolite bile acids and oxidative metabolism. These as well as other candidates will be investigated by genetic and pharmacological perturbations in cell culture and in mouse models. Bioinformatics integration of the orthogonal profiling kinetics is expected to reveal novel properties of the molecular networks mediating between metabolism and inflammation.
This proposed cross-disciplinary approach aims to improve our understanding of the crosstalk of metabolism and inflammation. The results of this project may be relevant to viral hepatitis in man and bear broader implications for other inflammatory diseases.
Summary
Inflammation is a response to noxious stimuli and initiates tissue repair. If resolution fails, however, chronic inflammation develops, which drives tissue damage in many diseases including autoimmunity, cancer and infections. Inflammatory processes are increasingly being appreciated as tightly integrated with metabolic pathways. The molecular crosstalk occurs on different levels including secreted metabolites and cytokines. I hypothesise that this interface of metabolism and inflammation represents a functional rheostat that shapes tissue damage and disease.
Here, I propose to analyse the metabolic and inflammatory processes in a mouse model of chronic viral hepatitis. I chose this model to explore the inflammatory rheostat because the liver is the central organ for metabolism and a hotspot for receiving, processing and distributing local and systemic signals. Cutting-edge technologies including deep sequencing, quantitative proteomics and metabolomics will let us create longitudinal multi-dimensional maps of virus-induced alterations. Paired with immunological, virological and pathological analyses, I expect to identify novel regulatory nodes between metabolism and inflammation. Within our systems-wide experiments and supported by preliminary results, we will specifically focus on the immunomodulatory roles of the metabolite bile acids and oxidative metabolism. These as well as other candidates will be investigated by genetic and pharmacological perturbations in cell culture and in mouse models. Bioinformatics integration of the orthogonal profiling kinetics is expected to reveal novel properties of the molecular networks mediating between metabolism and inflammation.
This proposed cross-disciplinary approach aims to improve our understanding of the crosstalk of metabolism and inflammation. The results of this project may be relevant to viral hepatitis in man and bear broader implications for other inflammatory diseases.
Max ERC Funding
1 701 011 €
Duration
Start date: 2016-04-01, End date: 2021-03-31
Project acronym Danger ATP
Project Regulation of inflammatory response by extracellular ATP and P2X7 receptor signalling: through and beyond the inflammasome
Researcher (PI) Pablo Pelegrin Vivancos
Host Institution (HI) FUNDACION PARA LA FORMACION E INVESTIGACION SANITARIAS DE LA REGION DE MURCIA
Call Details Consolidator Grant (CoG), LS6, ERC-2013-CoG
Summary Inflammatory diseases affect over 80 million people worldwide and accompany many diseases of industrialized countries, being the majority of them infection-free conditions. There are few efficient anti-inflammatory drugs to treat chronic inflammation and thus, there is an urgent need to validate novel targets. We now know that innate immunity is the main coordinator and driver of inflammation. Recently, we and others have shown that the activation of purinergic P2X7 receptors (P2X7R) in immune cells is a novel and increasingly validated pathway to initiate inflammation through the activation of the NLRP3 inflammasome and the release of IL-1β and IL-18 cytokines. However, how NLRP3 sense P2X7R activation is not fully understood. Furthermore, extracellular ATP, the physiological P2X7R agonist, is a crucial danger signal released by injured cells, and one of the most important mediators of infection-free inflammation. We have also identified novel signalling roles for P2X7R independent on the NLRP3 inflammasome, including the release of proteases or inflammatory lipids. Therefore, P2X7R has generated increasing interest as a therapeutic target in inflammatory diseases, being drug like P2X7R antagonist in clinical trials to treat inflammatory diseases. However, it is often questioned the functionality of P2X7R in vivo, where it is thought that extracellular ATP levels are below the threshold to activate P2X7R. The overall significance of this proposal relays to elucidate how extracellular ATP controls host-defence in vivo, ultimately depicting P2X7R signalling through and beyond inflammasome activation. We foresee that our results will generate a leading innovative knowledge about in vivo extracellular ATP signalling during the host response to infection and sterile danger.
Summary
Inflammatory diseases affect over 80 million people worldwide and accompany many diseases of industrialized countries, being the majority of them infection-free conditions. There are few efficient anti-inflammatory drugs to treat chronic inflammation and thus, there is an urgent need to validate novel targets. We now know that innate immunity is the main coordinator and driver of inflammation. Recently, we and others have shown that the activation of purinergic P2X7 receptors (P2X7R) in immune cells is a novel and increasingly validated pathway to initiate inflammation through the activation of the NLRP3 inflammasome and the release of IL-1β and IL-18 cytokines. However, how NLRP3 sense P2X7R activation is not fully understood. Furthermore, extracellular ATP, the physiological P2X7R agonist, is a crucial danger signal released by injured cells, and one of the most important mediators of infection-free inflammation. We have also identified novel signalling roles for P2X7R independent on the NLRP3 inflammasome, including the release of proteases or inflammatory lipids. Therefore, P2X7R has generated increasing interest as a therapeutic target in inflammatory diseases, being drug like P2X7R antagonist in clinical trials to treat inflammatory diseases. However, it is often questioned the functionality of P2X7R in vivo, where it is thought that extracellular ATP levels are below the threshold to activate P2X7R. The overall significance of this proposal relays to elucidate how extracellular ATP controls host-defence in vivo, ultimately depicting P2X7R signalling through and beyond inflammasome activation. We foresee that our results will generate a leading innovative knowledge about in vivo extracellular ATP signalling during the host response to infection and sterile danger.
Max ERC Funding
1 794 948 €
Duration
Start date: 2014-09-01, End date: 2019-08-31
