The UPEC Pore-Forming Toxin α-Hemolysin Triggers Proteolysis of Host Proteins to Disrupt Cell Adhesion, Inflammatory, and Survival Pathways

Dhakal, Bijaya K.; Mulvey, Matthew

doi:10.1016/j.chom.2011.12.003

Cited by 157 publications

(155 citation statements)

References 70 publications

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“…One possible explanation is that HlyA disrupts NF-kB signaling via activation of host serine proteases as described during UTI. 30 Such a hypothesis is consistent with our findings that HlyA acts downstream from the activation of Rac and upstream from the secretion of IL-1beta. This provides further evidence of the importance of pathogens to target the caspase-1/IL-1beta signaling axis.…”

Section: Neutralizing Rho Gtpases Downstream Effects To Block Avi Andsupporting

confidence: 90%

Switching Rho GTPase activation into effective antibacterial defenses requires the caspase-1/IL-1beta signaling axis

Boyer

Lemichez²

2015

Small GTPases

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Section: Neutralizing Rho Gtpases Downstream Effects To Block Avi Andsupporting

confidence: 90%

Switching Rho GTPase activation into effective antibacterial defenses requires the caspase-1/IL-1beta signaling axis

Boyer

Lemichez²

2015

Small GTPases

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“…HlyA-positive isolates have been shown to stimulate more rapid and extensive shedding of human BECs than isogenic hlyA-negative mutant strains (11,12). HlyA-mediated exfoliation is, in part, due to its ability to trigger degradation of paxillin, a scaffold protein that can modulate the dynamics of cytoskeletal rearrangements (14). Here, we discovered that overexpression of the hlyA gene in UPEC triggers urothelial cell death and release of IL-1α via hCaspase-4 activation and Caspase-1-dependent IL-1β secretion via activation of the NLRP3 inflammasome pathway to orchestrate additional cell death.…”

Section: Overproduction Of Hlya Increases Bladder Inflammasome Activamentioning

confidence: 99%

“…HlyA can form pores in the membranes and lyse a number of mammalian cell types, including RBCs (13). Recent studies have shown that HlyA can trigger rapid degradation of paxillin and other host proteins involved in cell-cell and cell-matrix interactions, a mechanism thought to promote exfoliation (14). In Staphylococcus aureus, hemolysins in the presence of lipoproteins promote the activation of Caspase-1 via the inflammasome in monocytic cells (15).…”

mentioning

confidence: 99%

Dysregulation ofEscherichia coliα-hemolysin expression alters the course of acute and persistent urinary tract infection

Nagamatsu¹,

Hannan

Guest

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

142

160

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Urinary tract infections (UTIs) are among the most common bacterial infections, causing considerable morbidity in females. Infection is highly recurrent despite appropriate antibiotic treatment. Uropathogenic Escherichia coli (UPEC), the most common causative agent of UTIs, invades bladder epithelial cells (BECs) and develops into clonal intracellular bacterial communities (IBCs). Upon maturation, IBCs disperse, with bacteria spreading to neighboring BECs to repeat this cycle. This process allows UPEC to gain a foothold in the face of innate defense mechanisms, including micturition, epithelial exfoliation, and the influx of polymorphonuclear leukocytes. Here, we investigated the mechanism and dynamics of urothelial exfoliation in the early acute stages of infection. We show that UPEC α-hemolysin (HlyA) induces Caspase-1/Caspase-4-dependent inflammatory cell death in human urothelial cells, and we demonstrate that the response regulator (CpxR)-sensor kinase (CpxA) two-component system (CpxRA), which regulates virulence gene expression in response to environmental signals, is critical for fine-tuning HlyA cytotoxicity. Deletion of the cpxR transcriptional response regulator derepresses hlyA expression, leading to enhanced Caspase-1/Caspase-4-and NOD-like receptor family, pyrin domain containing 3-dependent inflammatory cell death in human urothelial cells. In vivo, overexpression of HlyA during acute bladder infection induces more rapid and extensive exfoliation and reduced bladder bacterial burdens. Bladder fitness is restored fully by inhibition of Caspase-1 and Caspase-11, the murine homolog of Caspase-4. Thus, we have discovered that fine-tuning of HlyA expression by the CpxRA system is critical for enhancing UPEC fitness in the urinary bladder. These results have significant implications for our understanding of how UPEC establishes persistent colonization. microbial pathogenesis | urinary tract infection | uropathogenic E. coli | persistent colonization

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“…28, 2018; (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. constructed by introducing into the wild-type strain (EIB202, CCTCC M208068) the plasmid 632 of pSF4000-hlyBACD (Dhakal & Mulvey, 2012) into UPEC UT189, EHEC EDL933 (Burgos et 633 al, 2009), EPEC (E. coli O26) (Schmidt et al, 1995) and K12, respectively. 634 .…”

Section: Conflict Of Interest 389mentioning

confidence: 99%

Hemolysin liberates bacterial outer membrane vesicles for cytosolic lipopolysaccharide sensing

Liu

Chen

Yang

et al. 2018

Preprint

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17Inflammatory caspase-11/4/5 recognize cytosolic LPS from invading Gram-negative bacteria and 18 induce pyroptosis and cytokine release, forming rapid innate antibacterial defenses. Since 19 extracellular or vacuole-constrained bacteria are thought to rarely access the cytoplasm, how their 20 LPS are exposed to the cytosolic sensors is a critical event for pathogen recognition. Hemolysin is 21 a pore-forming bacterial toxin, which was generally accepted to rupture cell membrane, leading to 22 cell lysis. Whether and how hemolysin participates in non-canonical inflammasome signaling 23 remains uncovered. Here, we show that hemolysin-overexpressed enterobacteria triggered 24 significantly increased caspase-4 activation in human intestinal epithelial cells (IECs). Hemolysin 25 promoted LPS cytosolic delivery from extracellular bacteria through dynamin-dependent 26 endocytosis. Further, we revealed that hemolysin was largely associated with bacterial outer 27 membrane vesicles (OMVs) and induced rupture of OMV-containing vacuoles, subsequently 28 increasing LPS exposure to the cytosolic sensor. Accordingly, overexpression of hemolysin 29 promoted caspase-11 dependent IL-18 secretion, gut inflammation, and enterocyte pyroptosis in 30 orally-infected mice, which was associated with restricting bacterial colonization in vivo. Together, 31 our work reveals a concept that hemolysin promotes noncanonical inflammasome activation via 32 liberating OMVs for cytosolic LPS sensing, which offers insights into innate immune surveillance 33 of dysregulated hemolysin via caspase-11/4 in intestinal antibacterial defenses. 34 Keywords: hemolysin, OMVs, noncanonical inflammasome, intestinal infection 35 36. CC-BY 4.0 International license It is made available under a (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/290445 doi: bioRxiv preprint first posted online Mar. 28, 2018; 3 Significance 37 Sensing of lipopolysaccharide (LPS) in the cytosol triggers non-canonical 38inflammasome-mediated innate responses. Recent work revealed that bacterial outer membrane 39 vesicles (OMVs) enables LPS to access the cytosol for extracellular bacteria. However, since 40 intracellular OMVs are generally constrained in endosomes, how OMV-derived LPS gain access 41 to the cytosol remains unknown. Here, we reported that hemolysin largely bound with OMVs and 42 entered cells through dynamin-dependent endocytosis. Intracellular hemolysin significantly 43 impaired OMVs-constrained vacuole integrity and increased OMV-derived LPS exposure to the 44 cytosolic sensor, which promoted non-canonical inflammasome activation and restricted bacterial 45 gut infections. This work reveals the role of hemolysin in promoting non-canonical inflammasome 46 activation and alerting host immune recognition, which provides insights into the more 47 sophisticated biological functions of hemolysin upon infection.

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The UPEC Pore-Forming Toxin α-Hemolysin Triggers Proteolysis of Host Proteins to Disrupt Cell Adhesion, Inflammatory, and Survival Pathways

Cited by 157 publications

References 70 publications

Switching Rho GTPase activation into effective antibacterial defenses requires the caspase-1/IL-1beta signaling axis

Switching Rho GTPase activation into effective antibacterial defenses requires the caspase-1/IL-1beta signaling axis

Dysregulation ofEscherichia coliα-hemolysin expression alters the course of acute and persistent urinary tract infection

Hemolysin liberates bacterial outer membrane vesicles for cytosolic lipopolysaccharide sensing

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