The importance of calcium influx, calpain and calmodulin for the activation of CaCo-2 cell death pathways by Clostridium perfringens enterotoxin

Chakrabarti, Ganes; McClane, Bruce A.

doi:10.1111/j.1462-5822.2004.00442.x

Cited by 103 publications

(108 citation statements)

References 62 publications

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“…This pore-forming toxin induces intracellular Ca 2ϩ oscillation process and sustained entry of Ca 2ϩ , which can activate the caspase-mediated apoptotic pathway. 40 According to this view, the pan-caspase inhibitor Z-VAD.fmk protects MCD cells against the cytotoxic action of CFT073. These findings contrast with those of Wu et al 41 using Madin-Darby canine kidney (MDCK) cells, which remained impermeant to the apical addition of UPEC, unless the cell polarity was disrupted by pretreating cells with the hepatocyte growth factor.…”

Section: Discussionmentioning

confidence: 99%

TLR4 Facilitates Translocation of Bacteria across Renal Collecting Duct Cells

Chassin¹,

Vimont²,

Cluzeaud³

et al. 2008

Journal of the American Society of Nephrology

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Uropathogenic Escherichia coli (UPEC) are the most frequent causes of urinary tract infections and pyelonephritis. Renal medullary collecting duct (MCD) cells are the intrarenal site to which UPEC strains prefer to adhere and initiate an inflammatory response, but the ability of UPEC strains to translocate across impermeant MCD cells has not been demonstrated definitively. Here, several UPEC strains adhered to the apical surface and translocated across confluent murine inner MCD cells grown on filters. UPEC strains expressing cytolytic and vacuolating cytotoxins disrupted the integrity of cell layers, whereas noncytolytic UPEC strains passed through the cell layers without altering tight junctions. Apical-to-basal transcellular translocation was dramatically reduced after extinction of Toll-like receptor 4 (TLR4) and the lipid raft marker caveolin-1 by small interfering RNA. Furthermore, disruption of lipid raft integrity by filipin III and methyl-␤-cyclodextrin significantly reduced both the transcellular translocation of UPEC across murine inner MCD cell layers and the stimulation of proinflammatory mediators. Bacterial translocation was also significantly reduced in primary cultures of TLR4-deficient mouse MCD cells compared with MCD cells from wild-type mice. Benzyl alcohol, an anesthetic that enhances membrane fluidity, favored the recruitment of caveolin-1 in lipid rafts and increased the translocation of UPEC across cultured TLR4-deficient MCD cells. These findings demonstrate that the transcellular translocation of UPEC strains across impermeant layers of MCD cells may occur through lipid rafts via a TLR4-facilitated process.

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Section: Discussionmentioning

confidence: 99%

TLR4 Facilitates Translocation of Bacteria across Renal Collecting Duct Cells

Chassin¹,

Vimont²,

Cluzeaud³

et al. 2008

Journal of the American Society of Nephrology

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“…CPE pore formation elevates cytoplasmic Ca 2ϩ levels, thereby triggering calmodulin-and calpain-dependent host cell death via either caspase 3-mediated apoptosis (low CPE doses) or oncosis (high CPE doses) (78,79). Ca 2ϩ entry also induces morphological damage that exposes the basolateral cell surface, allowing CPE to interact with claudins and another tight junction protein named occludin (74,80).…”

Section: Toxins That Can Be Either Chromosomally or Plasmid Encodedmentioning

confidence: 99%

Toxin Plasmids of Clostridium perfringens

Adams

Bannam

et al. 2013

Microbiol Mol Biol Rev

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225

282

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SUMMARY In both humans and animals, Clostridium perfringens is an important cause of histotoxic infections and diseases originating in the intestines, such as enteritis and enterotoxemia. The virulence of this Gram-positive, anaerobic bacterium is heavily dependent upon its prolific toxin-producing ability. Many of the ∼16 toxins produced by C. perfringens are encoded by large plasmids that range in size from ∼45 kb to ∼140 kb. These plasmid-encoded toxins are often closely associated with mobile elements. A C. perfringens strain can carry up to three different toxin plasmids, with a single plasmid carrying up to three distinct toxin genes. Molecular Koch's postulate analyses have established the importance of several plasmid-encoded toxins when C. perfringens disease strains cause enteritis or enterotoxemias. Many toxin plasmids are closely related, suggesting a common evolutionary origin. In particular, most toxin plasmids and some antibiotic resistance plasmids of C. perfringens share an ∼35-kb region containing a Tn 916 -related conjugation locus named tcp (transfer of clostridial plasmids). This tcp locus can mediate highly efficient conjugative transfer of these toxin or resistance plasmids. For example, conjugative transfer of a toxin plasmid from an infecting strain to C. perfringens normal intestinal flora strains may help to amplify and prolong an infection. Therefore, the presence of toxin genes on conjugative plasmids, particularly in association with insertion sequences that may mobilize these toxin genes, likely provides C. perfringens with considerable virulence plasticity and adaptability when it causes diseases originating in the gastrointestinal tract.

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“…This is followed by formation of SDS-resistant complexes of ϳ450 and ϳ600 kDa, which contains CPE and claudins; the ϳ600-kDa complex also contains a second tight junction transmembrane protein, occludin (5,6). These large complexes are thought to represent the cytotoxic pores, which create a hole in the plasma membrane and lead to cell death (7). The structure of CPE remains unknown, and this has slowed a more detailed understanding of its complex pathogenic mechanism.…”

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confidence: 99%

Structure of the Claudin-binding Domain of Clostridium perfringens Enterotoxin

Itallie¹,

Betts

Smedley

et al. 2008

Journal of Biological Chemistry

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100

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Clostridium perfringens enterotoxin is a common cause of food-borne and antibiotic-associated diarrhea. The toxin's receptors on intestinal epithelial cells include claudin-3 and -4, members of a large family of tight junction proteins. Toxin-induced cytolytic pore formation requires residues in the NH 2 -terminal half, whereas residues near the COOH terminus are required for binding to claudins. The claudin-binding COOHterminal domain is not toxic and is currently under investigation as a potential drug absorption enhancer. Because claudin-4 is overexpressed on some human cancers, the toxin is also being investigated for targeting chemotherapy. Our aim was to solve the structure of the claudin-binding domain to advance its therapeutic applications. The structure of a 14-kDa fragment containing residues 194 to the native COOH terminus at position 319 was solved by x-ray diffraction to a resolution of 1.75 Å . The structure is a nine-strand ␤ sandwich with previously unappreciated similarity to the receptor-binding domains of several other toxins of spore-forming bacteria, including the collagenbinding domain of ColG from Clostridium histolyticum and the large Cry family of toxins (including Cry4Ba) of Bacillus thuringiensis. Correlations with previous studies suggest that the claudin-4 binding site is on a large surface loop between strands ␤8 and ␤9 or includes these strands. The sequence that was crystallized (residues 194 -319) binds to purified human claudin-4 with a 1:1 stoichiometry and affinity in the submicromolar range similar to that observed for binding of native toxin to cells. Our results provide a structural framework to advance therapeutic applications of the toxin and suggest a common ancestor for several receptor-binding domains of bacterial toxins.

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The importance of calcium influx, calpain and calmodulin for the activation of CaCo-2 cell death pathways by Clostridium perfringens enterotoxin

Cited by 103 publications

References 62 publications

TLR4 Facilitates Translocation of Bacteria across Renal Collecting Duct Cells

TLR4 Facilitates Translocation of Bacteria across Renal Collecting Duct Cells

Toxin Plasmids of Clostridium perfringens

Structure of the Claudin-binding Domain of Clostridium perfringens Enterotoxin

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