Büro PER 03 - I.14
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Pathogenic microorganisms are a global major health threat that is alarmingly aggravated by the drastic increase in multidrug resistance in recent years. Our research focuses on cell-mediated immune mechanisms that restrict microbial infections. We recently discovered that the immune serine proteases of cytotoxic T and natural killer cells, the granzymes, exhibit potent antimicrobial activity by cleaving multiple vital protein substrates triggering rapid microbial death. We, thus, defined a novel immunological paradigm suggesting a crucial role of cytotoxic effector proteases in the immune defence against pathogenic microorganisms (Cell, 2014; Nature Medicine, 2016). Comprehensive proteomics and bioinformatics analysis of bacterial granzyme B substrates in the model pathogen Listeria monocytogenes revealed a highly targeted attack on protein networks that are up-regulated during infectious growth in vivo. This finding suggests an unexpected immune mechanism that specifically targets bacterial proteins directly related to virulence and pathogenicity. We will explore this recently discovered immune strategy by dissecting an evolutionarily conserved host-pathogen interaction, i.e. the immune proteases targeted destruction of proteins in clinically relevant pathogenic bacteria using well-established proteomics as well as bioinformatics tools. These data will provide an evolutionary insight of how to effectively kill bacterial pathogens and restrict infections. Malaria remains one of the most challenging health problems in developing countries. Plasmodium spp., the cause of malaria, have a complex life cycle. However, it is accepted that the exponential growth of the parasites in the blood is responsible for almost all the clinical symptoms of malaria and the associated morbidity and mortality. Therefore, to efficiently prevent malaria pathogenesis and progression toward severe disease, tight control of parasitemia is essential. In collaboration with Dr. Pierre-Yves Mantel, we plan to identify the cytotoxic lymphocyte populations capable to restrict the growth of Plasmodium in red blood cells and characterize the underlying mechanisms. Our preliminary data clearly indicate that the granzymes contribute crucially to the observed growth restriction in red blood cells. Therefore, we also aim to identify the molecular targets of the immune proteases in stage-specific proteomics screens.