Post-translational modifications in host cells during Klebsiella pneumoniae infections

• Main Author: Przybyszewska, Kornelia Natalia
• Published: Queen's University Belfast 2017
• Subjects: 616.2
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.728394

Bacterial pathogens have developed a range of strategies to counteract the immune system. An emerging field is the manipulation of post-translational modifications by pathogens to affect hundreds, if not thousands of different proteins, leading to a dramatic impact on the biology of the cell. The human pathogen Klebsiella pneumoniae, a source of nosocomial and community-acquired pneumonia and urinary tract infections, limits the activation of the NF-KB-governed host defence mechanisms. Mechanistically, K. pneumoniae blocks the ubiquitination of TRAF6 by up-regulating the deubiquitinase CYLD. This study focuses on the manipulation of the ubiquitin-like processes SUMOylation, NEDDylation and ISGylation by Klebsiella. In this work, we show that each of these important processes is targeted by the pathogen. K. pneumoniae induces an overall decrease in SUMOylation in human epithelial cells in UBC9-independent manner, in contrast to all described bacterial pathogens. K. pneumoniae prevents the NEDDylation of the Cullin-1 protein, an essential component of ubiquitin ligation complex, disrupting ubiquitin-dependent signalling and proteasome degradation of proteins, like Ik-Bo and p-catenin. For the first time, molecular mechanisms of deNEDDylation of Cullin-1 was described, as a co-effect of reactive oxygen species and two deNEDDylases: SENP8 and CSN5 upon the infection. We demonstrate a decrease of ISGylation in K. pneumoniae infected epithelial cells, which suggests a block of interferon-dependent host responses. Moreover, we show implication of delSGylase UBP43 in the reduction of the proinflammatory responses in K. pneumoniae infected epithelium. This study, demonstrate an interferon type I and TLR4-dependent response against K. pneumoniae in macrophages, leading to ISGylation and secretion of the free ISG15 protein. Additionally, we included the preliminary data on the influence of K. pneumoniae infection on the mitochondrial network. Our data present a dramatic fragmentation of the mitochondrial network upon K. pneumoniae infection.