Project acronym CIRCODE
Project Cell-type specific mechanisms regulating rhythms in leukocyte homing
Researcher (PI) Christoph Andreas Scheiermann
Host Institution (HI) LUDWIG-MAXIMILIANS-UNIVERSITAET MUENCHEN
Call Details Starting Grant (StG), LS6, ERC-2014-STG
Summary Leukocytes are the key components of the immune system that fight infections and provide tissue repair, yet their migration patterns throughout the body over the course of a day are completely unknown. Circadian, ~24 hour rhythms are emerging as important novel regulators of immune cell migration and function, which impacts inflammatory diseases such as myocardial infarction and sepsis. Altering leukocyte tissue infiltration and activation at the proper times provides an option for therapy that would maximize the clinical impact of drugs and vaccinations and minimize side effects.
We aim to create a four-dimensional map of leukocyte migration to organs in time and space and investigate with epigenetics techniques the molecular mechanisms that regulate cell-type specific rhythms. We will functionally define the daily oscillating molecular signature(s) of leukocytes and endothelial cells with novel proteomics approaches and thus identify a circadian traffic code that dictates the rhythmic migration of leukocyte subsets to specific organs under steady-state and inflammatory conditions with pharmacological and genetic tools. We will assess the impact of lineage-specific arrhythmicities on immune homeostasis and leukocyte trafficking using an innovative combination of novel genetic tools. Based on these data we will create a model predicting circadian leukocyte migration to tissues.
The project combines the disciplines of immunology and chronobiology by obtaining unprecedented information in time and space of circadian leukocyte trafficking and investigating how immune-cell specific oscillations are generated at the molecular level, which is of broad impact for both fields. Our extensive experience in the rhythmic control of the immune system makes us well poised to characterize the molecular components that orchestrate circadian leukocyte distribution across the body.
Summary
Leukocytes are the key components of the immune system that fight infections and provide tissue repair, yet their migration patterns throughout the body over the course of a day are completely unknown. Circadian, ~24 hour rhythms are emerging as important novel regulators of immune cell migration and function, which impacts inflammatory diseases such as myocardial infarction and sepsis. Altering leukocyte tissue infiltration and activation at the proper times provides an option for therapy that would maximize the clinical impact of drugs and vaccinations and minimize side effects.
We aim to create a four-dimensional map of leukocyte migration to organs in time and space and investigate with epigenetics techniques the molecular mechanisms that regulate cell-type specific rhythms. We will functionally define the daily oscillating molecular signature(s) of leukocytes and endothelial cells with novel proteomics approaches and thus identify a circadian traffic code that dictates the rhythmic migration of leukocyte subsets to specific organs under steady-state and inflammatory conditions with pharmacological and genetic tools. We will assess the impact of lineage-specific arrhythmicities on immune homeostasis and leukocyte trafficking using an innovative combination of novel genetic tools. Based on these data we will create a model predicting circadian leukocyte migration to tissues.
The project combines the disciplines of immunology and chronobiology by obtaining unprecedented information in time and space of circadian leukocyte trafficking and investigating how immune-cell specific oscillations are generated at the molecular level, which is of broad impact for both fields. Our extensive experience in the rhythmic control of the immune system makes us well poised to characterize the molecular components that orchestrate circadian leukocyte distribution across the body.
Max ERC Funding
1 497 688 €
Duration
Start date: 2015-09-01, End date: 2020-08-31
Project acronym GAMES
Project Gut Microbiota in Nervous System Autoimmunity: Molecular Mechanisms of Disease Initiation and Regulation
Researcher (PI) Gurumoorthy Krishnamoorthy
Host Institution (HI) MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV
Call Details Starting Grant (StG), LS6, ERC-2014-STG
Summary Multiple Sclerosis (MS), an autoimmune demyelinating disease affecting the central nervous system (CNS), causes tremendous disability in young adults and inflicts huge economic burden on the society. The incidence of MS is steadily increasing in many countries arguing for environmental factors driven changes in disease induction. How and which environmental factors contribute to disease initiation and progression is unknown. Using a spontaneous mouse model of MS, we have shown that the gut microbiota is essential in triggering CNS autoimmunity. In contrast to the mice housed in conventional housing conditions, germ free (GF) mice, devoid of gut bacteria, were protected from spontaneous experimental autoimmune encephalomyelitis (sEAE). Re-colonization of GF mice with a complex regular gut flora derived from specific pathogen free (SPF) mice resulted in sEAE within 2-3 months. The re-colonization also triggered pro-inflammatory T and B cell responses. However, colonization of GF mice with a reduced gut flora failed to induce sEAE during our observation period suggesting a “specific” rather than a “broader” microbial trigger. In this proposal, I want to study the role of gut microbiota in CNS autoimmunity with the following aims:
Aim 1: CNS autoimmunity triggering/protecting gut microbes and host immune responses
I want to study how and which gut bacterial species are modulating CNS autoimmunity to better understand the origin of autoimmune responses and their relation to host immune responses.
Aim 2: Molecular mechanisms of sensing of gut microbiota and microbial metabolites during CNS autoimmunity
I want to identify the molecular pathways that are involved in sensing the gut microbiota and its metabolites which are relevant to CNS autoimmunity.
Aim 3: Therapeutic application of gut microbiota for CNS autoimmunity
I want to identify therapeutic strategies targeting gut microbiota to limit the development of inflammatory processes during CNS autoimmunity.
Summary
Multiple Sclerosis (MS), an autoimmune demyelinating disease affecting the central nervous system (CNS), causes tremendous disability in young adults and inflicts huge economic burden on the society. The incidence of MS is steadily increasing in many countries arguing for environmental factors driven changes in disease induction. How and which environmental factors contribute to disease initiation and progression is unknown. Using a spontaneous mouse model of MS, we have shown that the gut microbiota is essential in triggering CNS autoimmunity. In contrast to the mice housed in conventional housing conditions, germ free (GF) mice, devoid of gut bacteria, were protected from spontaneous experimental autoimmune encephalomyelitis (sEAE). Re-colonization of GF mice with a complex regular gut flora derived from specific pathogen free (SPF) mice resulted in sEAE within 2-3 months. The re-colonization also triggered pro-inflammatory T and B cell responses. However, colonization of GF mice with a reduced gut flora failed to induce sEAE during our observation period suggesting a “specific” rather than a “broader” microbial trigger. In this proposal, I want to study the role of gut microbiota in CNS autoimmunity with the following aims:
Aim 1: CNS autoimmunity triggering/protecting gut microbes and host immune responses
I want to study how and which gut bacterial species are modulating CNS autoimmunity to better understand the origin of autoimmune responses and their relation to host immune responses.
Aim 2: Molecular mechanisms of sensing of gut microbiota and microbial metabolites during CNS autoimmunity
I want to identify the molecular pathways that are involved in sensing the gut microbiota and its metabolites which are relevant to CNS autoimmunity.
Aim 3: Therapeutic application of gut microbiota for CNS autoimmunity
I want to identify therapeutic strategies targeting gut microbiota to limit the development of inflammatory processes during CNS autoimmunity.
Max ERC Funding
1 499 946 €
Duration
Start date: 2015-06-01, End date: 2020-05-31
Project acronym HIV1ABTHERAPY
Project Antibody-Mediated Therapy of HIV-1 Infection
Researcher (PI) Florian Klein
Host Institution (HI) KLINIKUM DER UNIVERSITAET ZU KOELN
Call Details Starting Grant (StG), LS6, ERC-2014-STG
Summary Antibodies are destined to neutralize pathogens and can prevent and fight infectious diseases. Over the last years, advances in single B cell cloning resulted in the isolation of highly potent and broad HIV-1 neutralizing antibodies (bNAbs) that have been shown to prevent SHIV infection in non-human primates (NHPs). Recently, we have demonstrated that a combination of bNAbs can suppress HIV-1 replication in humanized mice, reducing viremia to undetectable levels. Moreover, bNAb therapy of SHIV-infected NHPs induced a rapid decline in viremia, followed by a prolonged control due to the long half-life of the antibodies. While these results strongly encourage the clinical evaluation of bNAbs in HIV-1 therapy, it is of critical importance to understand how the therapeutic potential of antibodies can be harnessed in the most effective way. Therefore, we aim to: I.) Identify exceptionally potent HIV-1 neutralizing antibodies that will be a crucial component of immunotherapy. By establishing novel methods for single-cell sorting and high-throughput sequencing we want to identify bNAbs targeting novel epitopes. II.) Prevent HIV-1 escape applying rationally designed treatment strategies targeting conserved functional sites for HIV-1 entry. III.) Evaluate immune markers and function in relation to bNAb administration in humans. Being at the forefront of one of the first clinical trials studying an HIV-1-directed bNAb, we will have the unique opportunity to investigate the interplay of antibody therapy and the host immune system. This proposal aims to strongly advance the field of HIV-1 antibody therapy and therefore enable the introduction of a new therapeutic modality for HIV-1, and will gain insights for antibody-mediated therapy in other infectious diseases.
Summary
Antibodies are destined to neutralize pathogens and can prevent and fight infectious diseases. Over the last years, advances in single B cell cloning resulted in the isolation of highly potent and broad HIV-1 neutralizing antibodies (bNAbs) that have been shown to prevent SHIV infection in non-human primates (NHPs). Recently, we have demonstrated that a combination of bNAbs can suppress HIV-1 replication in humanized mice, reducing viremia to undetectable levels. Moreover, bNAb therapy of SHIV-infected NHPs induced a rapid decline in viremia, followed by a prolonged control due to the long half-life of the antibodies. While these results strongly encourage the clinical evaluation of bNAbs in HIV-1 therapy, it is of critical importance to understand how the therapeutic potential of antibodies can be harnessed in the most effective way. Therefore, we aim to: I.) Identify exceptionally potent HIV-1 neutralizing antibodies that will be a crucial component of immunotherapy. By establishing novel methods for single-cell sorting and high-throughput sequencing we want to identify bNAbs targeting novel epitopes. II.) Prevent HIV-1 escape applying rationally designed treatment strategies targeting conserved functional sites for HIV-1 entry. III.) Evaluate immune markers and function in relation to bNAb administration in humans. Being at the forefront of one of the first clinical trials studying an HIV-1-directed bNAb, we will have the unique opportunity to investigate the interplay of antibody therapy and the host immune system. This proposal aims to strongly advance the field of HIV-1 antibody therapy and therefore enable the introduction of a new therapeutic modality for HIV-1, and will gain insights for antibody-mediated therapy in other infectious diseases.
Max ERC Funding
1 500 000 €
Duration
Start date: 2016-01-01, End date: 2020-12-31
Project acronym SOS
Project Sorting of Self
Researcher (PI) Gerhard Krönke
Host Institution (HI) UNIVERSITATSKLINIKUM ERLANGEN
Call Details Starting Grant (StG), LS6, ERC-2014-STG
Summary During inflammation and infection, we are simultaneously confronted with both self and non-self in form of dying cells and microbes, respectively. Mechanisms that facilitate the non-immunogenic clearance of self-antigens derived from apoptotic and necrotic cells and that, in parallel, allow the initiation of an immune response against invading pathogens are incompletely understood.
Recent data from our laboratory show that the immune system actively sorts apoptotic cells (ACs) and bacteria into distinct subspecies of macrophages and dendritic cells thereby enabling a segregated processing of self and non-self as well as a differential immune response against these two entities. Incorrect sorting and aberrant uptake of AC-derived self-antigens by pro-inflammatory and antigen-presenting dendritic cells, however, results in the break of self-tolerance and autoimmunity.
Due to technical limitations, the identification and fate-mapping of specific phagocyte subsets that mediate the simultaneous clearance of dying cells and pathogens in vivo has remained largely elusive. We thus plan to develop novel tools that are based on cutting-edge technologies to comprehensively elucidate the sorting of dying cells and pathogens under inflammatory conditions in vivo. We plan to generate TAT-Cre transgenic mice and bacteria that will be used in conjunction with R26-eYFP reporter animals to permanently track phagocytes after ingestion of endogenously accumulated dying cells and pathogens, respectively. These approaches will enable us to characterize the involved phagocytes, study molecular mechanisms underlying the differential processing of self and non-self and follow the phagocyte’s migratory behaviour and its subsequent differentiation. The obtained data will not only provide insights into the pathogenesis of autoimmune and infectious diseases, but will also foster the development of novel therapeutic strategies for the treatment of such disorders.
Summary
During inflammation and infection, we are simultaneously confronted with both self and non-self in form of dying cells and microbes, respectively. Mechanisms that facilitate the non-immunogenic clearance of self-antigens derived from apoptotic and necrotic cells and that, in parallel, allow the initiation of an immune response against invading pathogens are incompletely understood.
Recent data from our laboratory show that the immune system actively sorts apoptotic cells (ACs) and bacteria into distinct subspecies of macrophages and dendritic cells thereby enabling a segregated processing of self and non-self as well as a differential immune response against these two entities. Incorrect sorting and aberrant uptake of AC-derived self-antigens by pro-inflammatory and antigen-presenting dendritic cells, however, results in the break of self-tolerance and autoimmunity.
Due to technical limitations, the identification and fate-mapping of specific phagocyte subsets that mediate the simultaneous clearance of dying cells and pathogens in vivo has remained largely elusive. We thus plan to develop novel tools that are based on cutting-edge technologies to comprehensively elucidate the sorting of dying cells and pathogens under inflammatory conditions in vivo. We plan to generate TAT-Cre transgenic mice and bacteria that will be used in conjunction with R26-eYFP reporter animals to permanently track phagocytes after ingestion of endogenously accumulated dying cells and pathogens, respectively. These approaches will enable us to characterize the involved phagocytes, study molecular mechanisms underlying the differential processing of self and non-self and follow the phagocyte’s migratory behaviour and its subsequent differentiation. The obtained data will not only provide insights into the pathogenesis of autoimmune and infectious diseases, but will also foster the development of novel therapeutic strategies for the treatment of such disorders.
Max ERC Funding
1 479 781 €
Duration
Start date: 2015-05-01, End date: 2020-04-30
Project acronym TEC_Pro
Project Molecular control of self-renewal and lineage specification in thymic epithelial cell progenitors in vivo.
Researcher (PI) Nuno Miguel De Oliveira Lages Alves
Host Institution (HI) INSTITUTO DE BIOLOGIA MOLECULAR E CELULAR-IBMC
Call Details Starting Grant (StG), LS6, ERC-2014-STG
Summary The development of vaccines for the treatment of infectious diseases, cancer and autoimmunity depends on our knowledge of T-cell differentiation. This proposal is focused on studying the thymus, the organ responsible for the generation of T cells that are responsive against pathogen-derived antigens, and yet tolerant to self. Within the thymus, thymic epithelial cells (TECs) provide key inductive microenvironments for the development and selection of T cells that arise from hematopoietic progenitors. As a result, defects in TEC differentiation cause syndromes that range from immunodeficiency to autoimmunity, which makes the study of TECs of fundamental, and clinical, importance to understand immunity and tolerance induction. TECs are divided into two functionally distinct cortical (cTECs) and medullary (mTECs) subtypes, which derive from common bipotent TEC progenitors (TEPs). Yet, the genetic and epigenetic details that control cTEC/mTEC lineage specifications from TEPs are unsettled.
My objectives are to identify TEC progenitors and their niches within the thymus, define new molecular components involved in their self-renewal and lineage potential, and elucidate the epigenetic codes that regulate the genetic programs during cTEC/mTEC fate decisions. We take a global approach to examine TEC differentiation, which integrates the study of molecular processes taking place at cellular level and the analysis of in vivo mouse models. Using advanced research tools that combine reporter mice, clonogenic assays, organotypic cultures, high-throughput RNAi screen and genome-wide epigenetic and transcriptomic profiling, we will dissect the principles that underlie the self-renewal and lineage differentiation of TEC progenitors in vivo. I believe this project has the potential to contribute to one of the great challenges of modern immunology – modulate thymic function through the induction of TEPs - and therefore, represents a major advance in Health Sciences.
Summary
The development of vaccines for the treatment of infectious diseases, cancer and autoimmunity depends on our knowledge of T-cell differentiation. This proposal is focused on studying the thymus, the organ responsible for the generation of T cells that are responsive against pathogen-derived antigens, and yet tolerant to self. Within the thymus, thymic epithelial cells (TECs) provide key inductive microenvironments for the development and selection of T cells that arise from hematopoietic progenitors. As a result, defects in TEC differentiation cause syndromes that range from immunodeficiency to autoimmunity, which makes the study of TECs of fundamental, and clinical, importance to understand immunity and tolerance induction. TECs are divided into two functionally distinct cortical (cTECs) and medullary (mTECs) subtypes, which derive from common bipotent TEC progenitors (TEPs). Yet, the genetic and epigenetic details that control cTEC/mTEC lineage specifications from TEPs are unsettled.
My objectives are to identify TEC progenitors and their niches within the thymus, define new molecular components involved in their self-renewal and lineage potential, and elucidate the epigenetic codes that regulate the genetic programs during cTEC/mTEC fate decisions. We take a global approach to examine TEC differentiation, which integrates the study of molecular processes taking place at cellular level and the analysis of in vivo mouse models. Using advanced research tools that combine reporter mice, clonogenic assays, organotypic cultures, high-throughput RNAi screen and genome-wide epigenetic and transcriptomic profiling, we will dissect the principles that underlie the self-renewal and lineage differentiation of TEC progenitors in vivo. I believe this project has the potential to contribute to one of the great challenges of modern immunology – modulate thymic function through the induction of TEPs - and therefore, represents a major advance in Health Sciences.
Max ERC Funding
1 491 749 €
Duration
Start date: 2015-07-01, End date: 2020-06-30
