Projects & Collaborations 4 foundShow per page10 10 20 50 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. Patient-reported symptom monitoring in aplastic anemia and paroxysmal nocturnal hemoglobinuria Research Project | 12 Project MembersNo Description available Analysis of T cell-dependent immunity during in vivo microbial infections Research Project | 2 Project MembersWithin this colaboration we aim to analyze T cell-dependent immunity during in vivo microbial infections Relevance of different CD4+ Tcell subsets for antifungal defense. What is aberrant in immunocompromised patients?" Research Project | 1 Project MembersThe incidence of opportunistic fungal infections caused in particular by Aspergillus fumigatus and Candida species has increased over the last decades. These infections have earlier been a leading cause of morbidity and mortality in patients with HIV/AIDS and have now become most prevalent in patients suffering from leukemia and in patients receiving allogeneic hematopoietic stem cell transplantation (HSCT), solid organ transplantation (SOT) or immunosuppressive treatment 1 , 2 . Despite antifungal prophylaxis or treatment, the therapeutic efficacy is often limited due to impaired host immunity, difficulties encountered in rapid and accurate diagnosis, emergence of uncommon or resistant pathogens, drug interactions and toxicity 2 . Hence, specific immunological markers that predict development and outcome as well as alternative treatment approaches that could restore or boost fungus-specific immunity would be desirable for these patients. Adoptive T-cell therapy for fungal infections is promising but little is known regarding the protective immune response in humans 3 . In mice, distinct CD4 + T-helper (T H ) subsets are important for host responses against fungi. Coordinated activation of T H 1 immunity, regulatory T cells and probably T H 17 cells seems to be necessary for pathogen control by enhancing the innate immune cells, whereas activation of T H 2 cells often exacerbates disease 4 , 5 . Therefore, understanding the mechanisms enhancing protective and/or dampening counteractive T H subsets may help to prevent or treat local and disseminated fungal infections in humans, which is particularly important in the development of immunotherapeutic approaches such as adoptive T-cell therapy or when identifying immunomodulatory compounds 6 , 7 . Although the time course of recovery of normal numbers of immune cells is well known for HSCT recipients or HIV-infected patients receiving antiretroviral therapy 8 , only little is known regarding possible qualitative impairments and the kinetics of recovery of the different fungus-specific T H subsets as well as the interaction of fungus-specific adaptive immunity with the cells of the innate immune system. As we have previously identified a T-cell epitope stimulating cross-reactive T cells that recognize A. fumigatus as well as C . albicans , we are able by using a MHC class II tetramer to directly monitor and track the recovery of these epitope-specific T cells in patients suffering from A. fumigatus or C. albicans infections and correlate it with clinical outcome 9 , 10 . Aims We aim to identify parameters of the antifungal immune response that correlate with the risk for developing invasive fungal infections (IFI) and/or the outcome of these infections. Further, we aim to increase and/or regulate antifungal T-cell immunity in immunocompromised patients either by adoptive transfer of fungus-specific T cells or by immunomodulatory compounds such as antifungal drugs, statins or vitamin D. Therefore, we need to characterise the different T H subsets involved in antifungal defence as well as their interaction with innate immunity in patients with disease compared to unaffected patients and healthy donors. Aim 1 To characterize the different T H subsets specific for A. fumigatus and C. albicans in healthy donors, their interplay with each other and with cells of the innate immune system as well as their ability to be modulated by different compounds. Aim 2 To identify qualitative and quantitative impairments of different T H subsets and/or innate immunity in HSCT recipients with IA in a nested unmatched case-control study. Aim 3 To assess qualitative and quantitative impairments of different T H subsets in HIV-infected patients with Candida esophagitis in a CD4 + T-cell matched nested case-control study. Relevance The current antifungal treatments are associated with high costs and yet with unsatisfactory outcome. Therefore, specific immunological parameters that influence outcome or correlate with the risk for developing IFI are of great interest to optimize treatment duration or to identify the need for prophylaxis. The development of anti-infective immunotherapeutic strategies is still at a very early stage and we hope and are confidential to make a valuable contribution in the understanding of the plasticity as well as cross-talk between different antigen-specific immune cells that have to be taken into consideration for successful intervention. The results of this study should provide the rational for immunomodulatory and immunotherapeutic strategies in patients at risk for IFI, which could complement or replace conventional antifungal therapy. 1 1
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.
Patient-reported symptom monitoring in aplastic anemia and paroxysmal nocturnal hemoglobinuria Research Project | 12 Project MembersNo Description available
Analysis of T cell-dependent immunity during in vivo microbial infections Research Project | 2 Project MembersWithin this colaboration we aim to analyze T cell-dependent immunity during in vivo microbial infections
Relevance of different CD4+ Tcell subsets for antifungal defense. What is aberrant in immunocompromised patients?" Research Project | 1 Project MembersThe incidence of opportunistic fungal infections caused in particular by Aspergillus fumigatus and Candida species has increased over the last decades. These infections have earlier been a leading cause of morbidity and mortality in patients with HIV/AIDS and have now become most prevalent in patients suffering from leukemia and in patients receiving allogeneic hematopoietic stem cell transplantation (HSCT), solid organ transplantation (SOT) or immunosuppressive treatment 1 , 2 . Despite antifungal prophylaxis or treatment, the therapeutic efficacy is often limited due to impaired host immunity, difficulties encountered in rapid and accurate diagnosis, emergence of uncommon or resistant pathogens, drug interactions and toxicity 2 . Hence, specific immunological markers that predict development and outcome as well as alternative treatment approaches that could restore or boost fungus-specific immunity would be desirable for these patients. Adoptive T-cell therapy for fungal infections is promising but little is known regarding the protective immune response in humans 3 . In mice, distinct CD4 + T-helper (T H ) subsets are important for host responses against fungi. Coordinated activation of T H 1 immunity, regulatory T cells and probably T H 17 cells seems to be necessary for pathogen control by enhancing the innate immune cells, whereas activation of T H 2 cells often exacerbates disease 4 , 5 . Therefore, understanding the mechanisms enhancing protective and/or dampening counteractive T H subsets may help to prevent or treat local and disseminated fungal infections in humans, which is particularly important in the development of immunotherapeutic approaches such as adoptive T-cell therapy or when identifying immunomodulatory compounds 6 , 7 . Although the time course of recovery of normal numbers of immune cells is well known for HSCT recipients or HIV-infected patients receiving antiretroviral therapy 8 , only little is known regarding possible qualitative impairments and the kinetics of recovery of the different fungus-specific T H subsets as well as the interaction of fungus-specific adaptive immunity with the cells of the innate immune system. As we have previously identified a T-cell epitope stimulating cross-reactive T cells that recognize A. fumigatus as well as C . albicans , we are able by using a MHC class II tetramer to directly monitor and track the recovery of these epitope-specific T cells in patients suffering from A. fumigatus or C. albicans infections and correlate it with clinical outcome 9 , 10 . Aims We aim to identify parameters of the antifungal immune response that correlate with the risk for developing invasive fungal infections (IFI) and/or the outcome of these infections. Further, we aim to increase and/or regulate antifungal T-cell immunity in immunocompromised patients either by adoptive transfer of fungus-specific T cells or by immunomodulatory compounds such as antifungal drugs, statins or vitamin D. Therefore, we need to characterise the different T H subsets involved in antifungal defence as well as their interaction with innate immunity in patients with disease compared to unaffected patients and healthy donors. Aim 1 To characterize the different T H subsets specific for A. fumigatus and C. albicans in healthy donors, their interplay with each other and with cells of the innate immune system as well as their ability to be modulated by different compounds. Aim 2 To identify qualitative and quantitative impairments of different T H subsets and/or innate immunity in HSCT recipients with IA in a nested unmatched case-control study. Aim 3 To assess qualitative and quantitative impairments of different T H subsets in HIV-infected patients with Candida esophagitis in a CD4 + T-cell matched nested case-control study. Relevance The current antifungal treatments are associated with high costs and yet with unsatisfactory outcome. Therefore, specific immunological parameters that influence outcome or correlate with the risk for developing IFI are of great interest to optimize treatment duration or to identify the need for prophylaxis. The development of anti-infective immunotherapeutic strategies is still at a very early stage and we hope and are confidential to make a valuable contribution in the understanding of the plasticity as well as cross-talk between different antigen-specific immune cells that have to be taken into consideration for successful intervention. The results of this study should provide the rational for immunomodulatory and immunotherapeutic strategies in patients at risk for IFI, which could complement or replace conventional antifungal therapy.
