Effects of purified Clostridium difficile toxin A on rabbit distal colon

Burakoff, Robert; Zhao, Liming; Celifarco, A; Rose, Kristine L.; Donovan, Virginia; Pothoulakis, Charalabos; Percy, W. H.

doi:10.1016/0016-5085(95)90320-8

Cited by 28 publications

(29 citation statements)

References 18 publications

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“…difficile infection supports the infiltration of many numbers of inflammatory cells such as neutrophils and lymphocytes into the mucosal layer (2,11,17). The present study demonstrated that human intestinal epithelial cells could express and secrete several CXC and CC chemokines.…”

Section: Discussionsupporting

confidence: 68%

“…On a single cell basis, neutrophils and lymphocytes may secrete small quantities of IFN-γ or TNF-α in response to toxin A stimulation. However, they constitute a majority of infiltrating cells in C. difficile-infected intestinal mucosa (2,11,17) and may be the major source of IFN-γ and TNF-α. This led us to hypothesize that the IFN-γ or TNF-α produced by the infiltrating immune cells may influence the neighboring mucosal epithelial cells.…”

Section: Discussionmentioning

confidence: 99%

“…These results suggest that the immune cells can produce IFN-γ or TNF-α in response to C. difficile infection, and those produced cytokines may influence the neighboring mucosal epithelial cells. Since a high population of lymphocytes is found in intestinal mucosa infected with C. difficile (2,11,17), we tested whether IFN-γ and TNF-α stimulation could influence CXC and CC chemokine release from C. difficile toxin A stimulated polarized epithelial cells. As shown in Fig.…”

Section: Ifn-γ and Tnf-α Increase The Basolateral Release Of CC Chemomentioning

confidence: 99%

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Differential Expression and Polarized Secretion of CXC and CC Chemokines by Human Intestinal Epithelial Cancer Cell Lines in Response to Clostridium difficile Toxin A

Kim

Jung

et al. 2002

Microbiology and Immunology

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Intestinal epithelial cells are the initial sites of host response to Clostridium difficile infection and can play a role in signaling the influx of inflammatory cells. To further explore this role, the regulated expression and polarized secretion of CXC and CC chemokines by human intestinal epithelial cells were investigated. An expression of the CXC chemokines, including IL‐8 and growth‐related oncogene (GRO)‐α, and the CC chemokine monocyte chemoattractant protein (MCP)‐1 from HT‐29 cells increased in the 1–6 hr following C. difficile toxin A stimulation, assessed by quantitative RT‐PCR. In contrast, the expression of neutrophil activating protein‐78 (ENA‐78) was delayed for 18 hr. The up‐regulated mRNA expression of chemokines was paralleled by the increase of protein levels. However, the expression of macrophage inflammatory protein (MIP)‐1α, RANTES (regulated on activation normal T cells expressed and secreted), and interferon‐γ‐inducible protein‐10 (IP‐10) was not changed in HT‐29 or Caco‐2 cells stimulated with toxin A. Upon stimulation of the polarized Caco‐2 epithelial cells in a transwell chamber with toxin A, CXC and CC chemokines were released predominantly into the basolateral compartment. Moreover, the addition of IFN‐γ and TNF‐α to toxin A stimulated Caco‐2 cells increased the basolateral release of CC chemokine MCP‐1. In contrast, IFN‐γ and TNF‐α had no effect on the expression of the CXC chemokines IL‐8 and GRO‐α. These results suggest that a CXC and CC chemokine expression from epithelial cells infected with C. difficile may be an important factor in the mucosal inflammatory response.

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Section: Discussionsupporting

confidence: 68%

Section: Discussionmentioning

confidence: 99%

Section: Ifn-γ and Tnf-α Increase The Basolateral Release Of CC Chemomentioning

confidence: 99%

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Differential Expression and Polarized Secretion of CXC and CC Chemokines by Human Intestinal Epithelial Cancer Cell Lines in Response to Clostridium difficile Toxin A

Kim

Jung

et al. 2002

Microbiology and Immunology

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“…This model involves the surgical generation of a terminal ileal ligation, termed the ileal loop, and administration of TcdA and/or TcdB into the lumen of the small intestine. Ileal loops have been used to assess toxin-induced inflammation and intestinal tissue damage in a number of species, including rabbits, rats, and mice (4,8,24,25,38,39,49). We, and others, have used this model in the mouse to characterize the inflammatory response and intestinal tissue damage triggered by TcdA and TcdB (13,19,36,49).…”

Section: Discussionmentioning

confidence: 99%

Intrarectal Instillation of Clostridium difficile Toxin A Triggers Colonic Inflammation and Tissue Damage: Development of a Novel and Efficient Mouse Model of Clostridium difficile Toxin Exposure

et al. 2012

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Clostridium difficile, a major cause of hospital-acquired diarrhea, triggers disease through the release of two toxins, toxin A (TcdA) and toxin B (TcdB). These toxins disrupt the cytoskeleton of the intestinal epithelial cell, increasing intestinal permeability and triggering the release of inflammatory mediators resulting in intestinal injury and inflammation. The most prevalent animal model to study TcdA/TcdB-induced intestinal injury involves injecting toxin into the lumen of a surgically generated "ileal loop." This model is time-consuming and exhibits variability depending on the expertise of the surgeon. Furthermore, the target organ of C. difficile infection (CDI) in humans is the colon, not the ileum. In the current study, we describe a new model of CDI that involves intrarectal instillation of TcdA/TcdB into the mouse colon. The administration of TcdA/TcdB triggered colonic inflammation and neutrophil and macrophage infiltration as well as increased epithelial barrier permeability and intestinal epithelial cell death. The damage and inflammation triggered by TcdA/TcdB isolates from the VPI and 630 strains correlated with the concentration of TcdA and TcdB produced. TcdA/TcdB exposure increased the expression of a number of inflammatory mediators associated with human CDI, including interleukin-6 (IL-6), gamma interferon (IFN-␥), and IL-1␤. Finally, we were able to demonstrate that TcdA was much more potent at inducing colonic injury than was TcdB but TcdB could act synergistically with TcdA to exacerbate injury. Taken together, our data indicate that the intrarectal murine model provides a robust and efficient system to examine the effects of TcdA/TcdB on the induction of inflammation and colonic tissue damage in the context of human CDI.

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“…Moreover, the experiments performed with anti-toxin A IgG2a imply that neutralization of toxin A might be sufficient to prevent initial damage and basolateral delivery of toxin B to its preferential site of action. Because toxin B has been shown to induce the release of proinflammatory cytokines and chemokines by lamina propria leukocytes, including mast cells (45), macrophages (46,47), and neutrophils (48,49), inhibition of its diffusion into the serosal compartment should reduce tissue damage and propagation of the bacterium.…”

Section: Discussionmentioning

confidence: 99%

Polymeric IgA Is Superior to Monomeric IgA and IgG Carrying the Same Variable Domain in Preventing Clostridium difficile Toxin A Damaging of T84 Monolayers

Stubbe¹,

Berdoz²,

Kraehenbuhl³

et al. 2000

The Journal of Immunology

101

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The two exotoxins A and B produced by Clostridium difficile are responsible for antibiotic-associated enterocolitis in human and animals. When added apically to human colonic carcinoma-derived T84 cell monolayers, toxin A, but not toxin B, abolished the transepithelial electrical resistance and altered the morphological integrity. Apical addition of suboptimal concentration of toxin A made the cell monolayer sensitive to toxin B. Both toxins induced drastic and rapid epithelial alterations when applied basolaterally with a complete disorganization of tight junctions and vacuolization of the cells. Toxin A-specific IgG2a from hybridoma PCG-4 added apically with toxin A alone or in combination with toxin B abolished the toxin-induced epithelial alterations for up to 8 h. The Ab neutralized basolateral toxin A for 4 h, but not the mixture of the two toxins. Using an identical Ab:Ag ratio, we found that recombinant polymeric IgA (IgAd/p) with the same Fv fragments extended protection against toxin A for at least 24 h in both compartments. In contrast, the recombinant monomeric IgA counterpart behaved as the PCG-4 IgG2a Ab. The direct comparison between different Ig isotype and molecular forms, but of unique specificity, demonstrates that IgAd/p Ab is more efficient in neutralizing toxin A than monomeric IgG and IgA. We conclude that immune protection against C. difficile toxins requires toxin A-specific secretory Abs in the intestinal lumen and IgAd/p specific for both toxins in the lamina propria.

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Effects of purified Clostridium difficile toxin A on rabbit distal colon

Cited by 28 publications

References 18 publications

Differential Expression and Polarized Secretion of CXC and CC Chemokines by Human Intestinal Epithelial Cancer Cell Lines in Response to Clostridium difficile Toxin A

Differential Expression and Polarized Secretion of CXC and CC Chemokines by Human Intestinal Epithelial Cancer Cell Lines in Response to Clostridium difficile Toxin A

Intrarectal Instillation of Clostridium difficile Toxin A Triggers Colonic Inflammation and Tissue Damage: Development of a Novel and Efficient Mouse Model of Clostridium difficile Toxin Exposure

Polymeric IgA Is Superior to Monomeric IgA and IgG Carrying the Same Variable Domain in Preventing Clostridium difficile Toxin A Damaging of T84 Monolayers

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