Enterohemorrhagic Escherichia coli O157 outer membrane vesicles induce interleukin 8 production in human intestinal epithelial cells by signaling via Toll-like receptors TLR4 and TLR5 and activation of the nuclear factor NF-κB

Role of Shiga Toxins in Cytotoxicity and Immunomodulatory Effects of Escherichia coli O157:H7 during Host-Bacterial Interactions in vitro

“…On the other hand, we showed that in vitro infection of HCT-8 cells with 125/99 strain triggers IL-8 secretion in line with previous reports [45,46]. Because IL-8 induces recruitment, activation, and migration of neutrophils to the intestine, it could contribute to disruption of epithelial integrity, increasing Stx absorption and thereby the pathogenicity of EHEC [47].…”

Secretion and Delivery of Intestinal Pathogenic Escherichia coli Virulence Factors via Outer Membrane Vesicles

“…In this regard, several investigations have demonstrated that budded portions of outer membrane material are shed also in vivo: vesicles produced by H. pylori were found in human gastric epithelium biopsies (Fiocca et al, 1999), and outer membrane protein-LPS complexes have been found in the sera of patients and rats with sepsis caused by Enterobacteriaceae (Hellman et al, 2000), in the plasma and the cerebrospinal fluid of patients with Neisseria meningitidis sepsis and meningitis, respectively (Stephens et al, 1982;Namork and Brandtzaeg, 2002), and in the nasal mucosa of a patient with sinusitis caused by M. catarrhalis (Tan et al, 2007). Vesicles from pathogenic strains such as Pseudomonas aeruginosa, H. pylori, A. actinomycetemcomitans, C. jejuni, S. enterica, V. cholera, and pathogenic E. coli contain active virulence factors, such as proteases, pro-inflammatory proteins, LPS, and toxins Beveridge, 1995, 1997;Kolling and Matthews, 1999;Horstman and Kuehn, 2000;Keenan and Allardyce, 2000;Kato et al, 2002;Wai et al, 2003;Kouokam et al, 2006;Lindmark et al, 2009;Ellis and Kuehn, 2010;Kaparakis et al, 2010;Chatterjee and Chaudhuri, 2011;Schaar et al, 2011;Rompikuntal et al, 2012Rompikuntal et al, , 2015Bielaszewska et al, 2013Bielaszewska et al, , 2017Bielaszewska et al, , 2018Guidi et al, 2013;Elluri et al, 2014;Thay et al, 2014;Kunsmann et al, 2015). However, the molecular mechanism of virulence factor delivery via vesicles has been unclear.…”

“…Intestinal pathogenic E. coli such as ETEC and EHEC produce OMVs under laboratory conditions as well as during infection (Wai et al, 1995;Kolling and Matthews, 1999;Horstman and Kuehn, 2000;Yokoyama et al, 2000;Aldick et al, 2009;Ellis and Kuehn, 2010;Bielaszewska et al, 2013Bielaszewska et al, , 2017Kunsmann et al, 2015;Bauwens et al, 2017b). Vesicles may contribute to the bacterial pathogenicity by serving as vehicles for toxin delivery into host cells Bielaszewska et al, 2013Bielaszewska et al, , 2017 as well as by inducing an inflammatory response, in particular secretion of interleukin 8 (IL-8) from intestinal epithelial cells (Kunsmann et al, 2015;Bielaszewska et al, 2018). Most vesicle proteins were resistant to dissociation, suggesting they were integral, or internal (Bielaszewska et al, 2013(Bielaszewska et al, , 2017.…”

“…Importantly, the report by Kim et al (2011) that EHEC O157 OMVs carrying Stx2a, the major EHEC virulence factor, elicited a HUS-like disease in a mouse model supports the hypothesis that OMVmediated secretion and delivery of EHEC toxins into host cells in vivo essentially contribute to the pathogenesis of EHEC infection. Besides their endothelial cytotoxicity, EHEC OMVs induce secretion of IL-8 from human intestinal epithelial cells (Kunsmann et al, 2015;Bielaszewska et al, 2018), which may also have pathogenetic implications since proinflammatory cytokines play multiple roles in the pathogenesis of HUS (Zoja et al, 2010;Karpman et al, 2017). A deeper analysis of OMVmediated IL-8 production demonstrated that flagellin and LPS are the key IL-8-inducing components of EHEC OMVs, and that flagellin-mediated signaling via TLR5, and LPS-mediated signaling via TLR4/MD-2 complex, followed by activation of the nuclear factor NF-κB, are the major pathways underlying IL-8 production (Kunsmann et al, 2015;Bielaszewska et al, 2018).…”

“…The potential of OMVs as offensive weapons is evident in their ability to deliver virulence factors into host cells ( Figure 1BIII) Tan et al, 2007;Bomberger et al, 2009;Amano et al, 2010;Ellis and Kuehn, 2010;Kulp and Kuehn, 2010;Schaar et al, 2011;Rompikuntal et al, 2012;Bielaszewska et al, 2013Bielaszewska et al, , 2017Kunsmann et al, 2015;O'Donoghue and Krachler, 2016;Rüter et al, 2018) as well as to induce sepsis, sepsis-associated cardiomyopathy or disseminated intravascular coagulation in the absence of intact bacterial cells (Park et al, 2010;Shah et al, 2012;Svennerholm et al, 2017;Wang et al, 2019). The OMVassociated LPS does not only appear to be effective through the extracellular Toll-like receptor (TLR) 4 (Kunsmann et al, 2015;Bielaszewska et al, 2018;Wang et al, 2019) or TLR2 (Schaar et al, 2011), as OMV-bound LPS can also activate the non-canonical inflammasome signaling pathway intracellularly after uptake of the OMVs into the target cells (Vanaja et al, 2016). The uptake of OMV occurs either by phagocytosis or by classic endocytosis Bielaszewska et al, 2013Bielaszewska et al, , 2017Rewatkar et al, 2015;O'Donoghue and Krachler, 2016), whereupon the virulence factors differentially separate during the intracellular transport of the OMVs and can develop their toxic activities (Bielaszewska et al, 2017).…”