Die Pathogenese der Escherichia coli-induzierten Sepsis in einem Immunoproteasom defizienten Mausmodell

The Pathogenesis of Escherichia coli induces Sepsis in an immunoproteasome deficient mouse model Sepsis is a life threatening organ dysfunction induced by a dysregulated immune reaction on an infectious agent and is the main reason for complications in intensive care units worldwide. Moreover, the septic shock, a sepsis underlying event caused by particularly profound circulatory, cellular and metabolic abnormalities is responsible for an in-hospital-mortality of al most 40 %. The incidence of this complex syndrome is rising due to sensitive diagnostics and the increasing rate of older and co-morbidity patients. Even successfully treated patients who survived sepsis suffer from long-time health restrictions. While sepsis is underestimated in public mind, it is a main issue in science due to the lack of adequate therapy options. Despite intense research it is of continual interest to find new results which are able to explain the diverse and complicated pathogenesis of sepsis and septic shock. This study is investigating the pathogenesis of the Gram-negative sepsis with the focus on an immune relevant subtype of the proteasome in a murine infection model. The proteasome is the major non-lysosomal protein degradation machinery in eukaryotic cells. Interferon γ and lipopolysaccharide, a cell wall component of gram-negative bacteria, cause a change in proteasome de novo composition and lead to an incorporation of proteolytic higher active immunosubunits. This study is investigating the immune modulatory function of this newly synthesized so called immunoproteasome (i-proteasome) during the infection of i-proteasome-knock-out-mice with Escherichia coli, the major representative pathogen causing Gram-negative sepsis. We observed severe symptoms and particularly profound organ damage in i-proteasome-knockout- mice forcing a multi-organ dysfunction syndrome and an accelerated lethality, indicating the crucial role of the i-proteasome during the pathogenesis of sepsis in this model. Nevertheless, neither the deficient eradication of this bacterial agent nor the higher bacterial burden found in the whole organism of knock-out-animals could be explained due to impaired function and quantity of innate immune cells at the site of infection. Furthermore, we noticed an unrestricted systemic production of pro- and anti-inflammatory mediators in i-proteasomeknock-out-mice. However, we identified an impaired lymphocytic immune response characterized by reduced lymphocyte counts and a diminished MHC-II-expression on B-cells of i-proteasome-knock-out-animals. Additionally, analyses of gene-expression in liver tissue of septic animals indicated differences in the transcriptomic profile between wild-type and iproteasome-knock-out-animals regarding groups of genes associated with angiogenesis, wound healing and apoptosis. These findings offer new insights in the immune modulatory role of the i-proteasome in Gram-negative sepsis and raise the hypothesis of a cell- and tissue specific function of the i-proteasome. Experiments of this study highlighted the protective character of the i-proteasome, particularly the immunosubunit Multicatalytic Endopeptidase Complex-1 (MECL-1) during the pathogenesis of Escherichia coli induced sepsis. As a consequence of this work we can conclude that the selective inhibition of the i-proteasome might not be a successful and clinically relevant pharmacological target to treat Gram-negative sepsis.