Short description
(English)
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The first line of defence facing invading bacteria are phagocytic cells of the innate immune system. These specialised cells can kill bacteria via oxygen-dependent (e.g. reactive oxygen species, ROS) and oxygenindependent (e.g. enzymes and microbicidal proteins) mechanisms. At the transition from monocellularity to multicellularity, eukaryotic organisms acquired NOX enzymes to generate ROS. In addition, phagocytosis of particles and bacteria is a key function of eukaryotic cells, conserved from amoebae to mammals. In amoebae, phagocytosis serves the purpose of nutrition, while in animal phagocytes uptake of bacteria leads to their killing and to antigen presentation to cells of the adaptive immune system. Therefore, the fundamental mechanisms of phagocytosis and mechanisms of bacteria killing (via NOX and other strategies) and digestion are highly conserved. However, some bacteria including Mycobacterium tuberculosis have developed survival strategies to resist killing by phagocytes. Overall, one key function of NOX enzymes lies in host defense, but many cells produce non-bactericidal levels of ROS, and despite intense research efforts, the understanding of ROS and NOX functions is still incomplete. We will use our simple and powerful experimental model system Dictyostelium infected with Mycobacterium marinum to dissect functions of ROS/NOX in host pathogen interactions, phagosomal bactericidal activities, including metal poisoning, but also in chemotaxis and morphogenesis.
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Abstract
(English)
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The first line of defence facing invading bacteria are phagocytic cells of the innate immune system. These specialised cells can kill bacteria via oxygen-dependent (e.g. reactive oxygen species, ROS) and oxygenindependent (e.g. enzymes and microbicidal proteins) mechanisms. At the transition from monocellularity to multicellularity, eukaryotic organisms acquired NOX enzymes to generate ROS. In addition, phagocytosis of particles and bacteria is a key function of eukaryotic cells, conserved from amoebae to mammals. In amoebae, phagocytosis serves the purpose of nutrition, while in animal phagocytes uptake of bacteria leads to their killing and to antigen presentation to cells of the adaptive immune system. Therefore, the fundamental mechanisms of phagocytosis and mechanisms of bacteria killing (via NOX and other strategies) and digestion are highly conserved. However, some bacteria including Mycobacterium tuberculosis have developed survival strategies to resist killing by phagocytes. Overall, one key function of NOX enzymes lies in host defense, but many cells produce non-bactericidal levels of ROS, and despite intense research efforts, the understanding of ROS and NOX functions is still incomplete. In this project, we use our simple and powerful experimental model system Dictyostelium to dissect the functions of ROS/NOX in host pathogen interactions, phagosomal bactericidal activities, and generation of DNA extracellular traps. The main advance has been in the generation of Dictyostelium strains with multiple knockouts in genes encoding NOX enzymes and regulatory proteins. We have also started analysing the regulators and effectors of the subcellular localisation of NOX, including the Dictyostelium ortholog of the Neutrophil Cytosolic Factor, NcfA.
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