Klebsiella pneumoniaereduces SUMOylation to limit host defence responses

Abstract

<jats:title>ABSTRACT</jats:title><jats:p><jats:italic>Klebsiella pneumoniae</jats:italic> is an important cause of multidrug resistant infections worldwide. Understanding the virulence mechanisms of <jats:italic>K. pneumoniae</jats:italic> is a priority and timely to design new therapeutics. Here we demonstrate that <jats:italic>K. pneumoniae</jats:italic> limits the SUMOylation of host proteins in epithelial cells and macrophages (mouse and human) to subvert cell innate immunity. Mechanistically, in lung epithelial cells <jats:italic>Klebsiella</jats:italic> increases the levels of the deSUMOylase SENP2 in the cytosol by affecting its K48-ubiquitylation and its subsequent degradation by the ubiquitin proteasome. This is dependent on <jats:italic>Klebsiella</jats:italic> preventing the NEDDylation of the Cullin-1 subunit of the ubiquitin ligase complex E3-SCFβ-TrCP by exploiting the CSN5 deNEDDylase. <jats:italic>Klebsiella</jats:italic> induces the expression of CSN5 in an EGFR-PI3K-AKT-ERK-GSK3β signalling pathway dependent manner. In macrophages, TLR4-TRAM-TRIF induced type-I IFN via IFNAR1-controlled signalling mediates <jats:italic>Klebsiella</jats:italic>-triggered decrease in the levels of SUMOylation via <jats:italic>let-7</jats:italic> miRNAs. Our results revealed the crucial role played by <jats:italic>Klebsiella</jats:italic> polysaccharides, the capsule and the LPS O-polysaccharide, to decrease the levels of SUMO-conjugated proteins in epithelial cells and macrophages. <jats:italic>Klebsiella</jats:italic>-induced decrease in SUMOylation promotes infection by limiting the activation of inflammatory responses and increasing intracellular survival in macrophages.</jats:p><jats:sec><jats:title>IMPORTANCE</jats:title><jats:p><jats:italic>Klebsiella pneumoniae</jats:italic> has been singled out as an urgent threat to human health due to the increasing isolation of strains resistant to “last line” antimicrobials, narrowing the treatment options against <jats:italic>Klebsiella</jats:italic> infections. Unfortunately, at present, we cannot identify candidate compounds in late-stage development for treatment of multidrug <jats:italic>Klebsiella</jats:italic> infections; this pathogen is exemplary of the mismatch between unmet medical needs and the current antimicrobial research and development pipeline. Furthermore, there is still limited evidence on <jats:italic>K. pneumoniae</jats:italic> pathogenesis at the molecular and cellular level in the context of the interactions between bacterial pathogens and their hosts. In this research, we have uncovered a sophisticated strategy employed by <jats:italic>Klebsiella</jats:italic> to subvert the activation of immune defences by controlling the modification of proteins. Our research may open opportunities to develop new therapeutics based on counteracting this <jats:italic>Klebsiella-</jats:italic>controlled immune evasion strategy.</jats:p></jats:sec>