Enteric pathogens, intestinal permeability and nitric oxide production in acute gastroenteritis

Kukuruzovic, Renata H; Robins-Browne, Roy M.; Anstey, Nicholas M.; Brewster, David

doi:10.1097/00006454-200208000-00007

Cited by 59 publications

(52 citation statements)

References 44 publications

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“…Many intracellular pathogens are killed by NO, but the role of NO in controlling infections of extracellular pathogens is not well established [19]. Interestingly, the NO levels in intestinal epithelial cells have also been shown to be important in the regulation of adsorption/secretion of water [41], suggesting that it could be associated with symptoms of giardiasis. The secreted OCT and ADI of Giardia might reduce the levels of intestinal arginine further and lower the NO production by IECs.…”

Section: Discussionmentioning

confidence: 99%

Release of metabolic enzymes by Giardia in response to interaction with intestinal epithelial cells

Ringqvist

Palm

Skarin

et al. 2008

Molecular and Biochemical Parasitology

154

139

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Giardia lamblia, an important cause of diarrheal disease, resides in the small intestinal lumen in close apposition to epithelial cells. Since the disease mechanisms underlying giardiasis are poorly understood, elucidating the specific interactions of the parasite with the host epithelium is likely to provide clues to understanding the pathogenesis. Here we tested the hypothesis that contact of Giardia lamblia with intestinal epithelial cells might lead to release of specific proteins. Using established co-culture models, intestinal ligated loops and a proteomics approach, we identified three G. lamblia proteins (arginine deiminase, ornithine carbamoyl transferase and enolase), previously recognized as immunodominant antigens during acute giardiasis. Release was stimulated by cell-cell interactions, since only small amounts of arginine deiminase and enolase were detected in the medium after culturing of G. lamblia alone. The secreted G. lamblia proteins were localized to the cytoplasm and the inside of the plasma membrane of trophozoites. Furthermore, in vitro studies with recombinant arginine deiminase showed that the secreted Giardia proteins can disable host innate immune factors such as nitric oxide production. These results indicate that contact of Giardia with epithelial cells triggers metabolic enzyme release, which might facilitate effective colonization of the human small intestine. a b s t r a c tGiardia lamblia, an important cause of diarrheal disease, resides in the small intestinal lumen in close apposition to epithelial cells. Since the disease mechanisms underlying giardiasis are poorly understood, elucidating the specific interactions of the parasite with the host epithelium is likely to provide clues to understanding the pathogenesis. Here we tested the hypothesis that contact of Giardia lamblia with intestinal epithelial cells might lead to release of specific proteins. Using established co-culture models, intestinal ligated loops and a proteomics approach, we identified three G. lamblia proteins (arginine deiminase, ornithine carbamoyl transferase and enolase), previously recognized as immunodominant antigens during acute giardiasis. Release was stimulated by cell-cell interactions, since only small amounts of arginine deiminase and enolase were detected in the medium after culturing of G. lamblia alone. The secreted G. lamblia proteins were localized to the cytoplasm and the inside of the plasma membrane of trophozoites. Furthermore, in vitro studies with recombinant arginine deiminase showed that the secreted Giardia proteins can disable host innate immune factors such as nitric oxide production. These results indicate that contact of Giardia with epithelial cells triggers metabolic enzyme release, which might facilitate effective colonization of the human small intestine.

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Section: Discussionmentioning

confidence: 99%

Release of metabolic enzymes by Giardia in response to interaction with intestinal epithelial cells

Ringqvist

Palm

Skarin

et al. 2008

Molecular and Biochemical Parasitology

154

139

View full text Add to dashboard Cite

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“…Intestinal permeability and motility are the two physiological mechanisms most rarely investigated, but currently they are being implicated in diarrheal syndromes (2,13). Intestinal permeability has only rarely been investigated in humans infected with RV (14). In the early 1980s, Stintzing and coworkers (15) assessed the intestinal permeability in young children with RV infection using polyethylene glycols (PEG) of different molecular weights, and a significantly low urinary recovery of PEG was noted.…”

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confidence: 99%

Rotavirus Infection Increases Intestinal Motility but Not Permeability at the Onset of Diarrhea

Istrate

Hagbom

Vikström

et al. 2014

J Virol

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The disease mechanisms associated with onset and secondary effects of rotavirus (RV) diarrhea remain to be determined and may not be identical. In this study, we investigated whether onset of RV diarrhea is associated with increased intestinal permeability and/or motility. To study the transit time, fluorescent fluorescein isothiocyanate (FITC)-dextran was given to RV-infected adult and infant mice. Intestinal motility was also studied with an opioid receptor agonist (loperamide) and a muscarinic receptor antagonist (atropine). To investigate whether RV increases permeability at the onset of diarrhea, fluorescent 4-and 10-kDa dextran doses were given to infected and noninfected mice, and fluorescence intensity was measured subsequently in serum. RV increased transit time in infant mice. Increased motility was detected at 24 h postinfection (h p.i.) and persisted up to 72 h p.i in pups. Both loperamide and atropine decreased intestinal motility and attenuated diarrhea. Analysis of passage of fluorescent dextran from the intestine into serum indicated unaffected intestinal permeability at the onset of diarrhea (24 to 48 h p.i.). We show that RV-induced diarrhea is associated with increased intestinal motility via an activation of the myenteric nerve plexus, which in turn stimulates muscarinic receptors on intestinal smooth muscles. IMPORTANCEWe show that RV-infected mice have increased intestinal motility at the onset of diarrhea, and that this is not associated with increased intestinal permeability. These new observations will contribute to a better understanding of the mechanisms involved in RV diarrhea.

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“…Similarly, expression of inducible NO synthase (iNOS) and synthesis of NO are significantly increased in intestinal mucosa from Cryptosporidium-infected piglets and mice (14,26,30). Induction of iNOS by or exposure of cell monolayers to high concentrations of NO promotes cytotoxicity and barrier disruption (4,36,43,44,47).…”

mentioning

confidence: 99%

“…Synthesis of nitric oxide (NO) is consistently elevated in patients with infectious diarrhea of a variety of causes (26), although its physiological value is unresolved. Similarly, expression of inducible NO synthase (iNOS) and synthesis of NO are significantly increased in intestinal mucosa from Cryptosporidium-infected piglets and mice (14,26,30).…”

mentioning

confidence: 99%

NF-κB-mediated expression of iNOS promotes epithelial defense against infection byCryptosporidium parvumin neonatal piglets

Gookin¹,

Chiang²,

Allen³

et al. 2006

American Journal of Physiology-Gastrointestinal and Liver Physi

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ridium sp. parasitizes intestinal epithelium, resulting in enterocyte loss, villous atrophy, and malabsorptive diarrhea. We have shown that mucosal expression of inducible nitric oxide (NO) synthase (iNOS) is increased in infected piglets and that inhibition of iNOS in vitro has no short-term effect on barrier function. NO exerts inhibitory effects on a variety of pathogens; nevertheless, the specific sites of iNOS expression, pathways of iNOS induction, and mechanism of NO action in cryptosporidiosis remain unclear. Using an in vivo model of Cryptosporidium parvum infection, we have examined the location, mechanism of induction, specificity, and consequence of iNOS expression in neonatal piglets. In acute C. parvum infection, iNOS expression predominated in the villous epithelium, was NF-B dependent, and was not restricted to infected enterocytes. Ongoing treatment of infected piglets with a selective iNOS inhibitor resulted in significant increases in villous epithelial parasitism and oocyst excretion but was not detrimental to maintenance of mucosal barrier function. Intensified parasitism could not be attributed to attenuated fluid loss or changes in epithelial proliferation or replacement rate, inasmuch as iNOS inhibition did not alter severity of diarrhea, piglet hydration, Cl Ϫ secretion, or kinetics of bromodeoxyuridine-labeled enterocytes. These findings suggest that induction of iNOS represents a nonspecific response of the epithelium that mediates enterocyte defense against C. parvum infection. iNOS did not contribute to the pathogenic sequelae of C. parvum infection. nitric oxide; barrier function; diarrhea; cryptosporidiosis A NONINVASIVE Protozoan, Cryptosporidium, parasitizes the small intestinal epithelium. Infection results in accelerated loss of villous enterocytes, leading to severe villous atrophy and a malabsorptive and secretory diarrhea. Acute epithelial defense against infection requires the elimination of parasitized enterocytes with preservation of epithelial continuity, as provided by enterocytes generated in the crypt and migrating onto the villus. These mechanisms must keep pace with ongoing infection until specific immune mechanisms result in clearance of the organisms. Surprisingly, little is known regarding the mechanisms and mediators of epithelial defense that predominate at the time of acute epithelial infection and diarrhea in the naturally susceptible host. Although studies in mice with defined immunodeficiency have identified a number of mediators (e.g., IFN-␥, CD40, and the CD4-positive T cell) that are necessary for onset of acquired immunity to chronic Cryptosporidium parvum infection, these animals do not develop villous atrophy or diarrhea, which characterize the acute clinical infection. Similarly, epithelial cell culture models of Cryptosporidium infection are unable to recapitulate the mechanisms of epithelial loss and replacement that characterize in vivo infection.Synthesis of nitric oxide (NO) is consistently elevated in patients with infectious diarrhea of a vari...

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Enteric pathogens, intestinal permeability and nitric oxide production in acute gastroenteritis

Abstract: Cryptosporidium, Strongyloides, rotavirus and enteroaggregative E. coli are important contributors to the severe manifestations of acute gastroenteritis in Australian Aboriginal children.

Cited by 59 publications

References 44 publications

Release of metabolic enzymes by Giardia in response to interaction with intestinal epithelial cells

Release of metabolic enzymes by Giardia in response to interaction with intestinal epithelial cells

Rotavirus Infection Increases Intestinal Motility but Not Permeability at the Onset of Diarrhea

NF-κB-mediated expression of iNOS promotes epithelial defense against infection byCryptosporidium parvumin neonatal piglets

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