Local Peroxynitrite Formation Contributes to Early Control of
            <i>Cryptosporidium parvum</i>
            Infection

Gookin, Jody L.; Allen, Julie K.; Chiang, Sophia; Duckett, Laurel L.; Armstrong, Martha U.

doi:10.1128/iai.73.7.3929-3936.2005

Cited by 21 publications

(19 citation statements)

References 40 publications

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“…Postulated mechanisms of NO antimicrobial action include inactivation of critical metabolic pathways through formation of iron-dinitrosyl-dithiolate complexes and generation of reactive nitrogen intermediates such as peroxynitrite (10,23). We recently showed that peroxynitrite is generated at sites of iNOS expression in C. parvum infection and that treatment with peroxynitrite scavengers similarly exacerbates C. parvum infection (13).…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…In AIDS patients with cryptosporidiosis, no correlation between neutrophilic inflammation and intensity of infection was found (23). On the other hand, antioxidants have been shown in several studies to exacerbate C. parvum infection (10,15,44). Whether neutrophils are the source of these antiparasitic oxidants has not been determined.…”

Section: Discussionmentioning

confidence: 99%

“…Probable cellular sources of superoxide for neutrophil recruitment in C. parvum infection include activated macrophages (28), intestinal epithelium, or vascular endothelium. A significant influx of macrophages has been demonstrated in the present model (17), and peroxynitrite, a reaction product of nitric oxide and superoxide, is generated at epithelial sites in C. parvum-infected mucosa (10). Inhibition of peroxynitrite formation is unlikely to be the means by which SOD inhibited neutrophil influx into C. parvum-infected mucosa, however, as superoxide reacts with NO at rates that exceed dismutation by SOD (31).…”

Section: Discussionmentioning

confidence: 99%

“…We have shown previously that the potent oxidant peroxynitrite is generated along the villus tips in C. parvum infection and in association with induction of inducible nitric oxide synthase (iNOS) expression (10). Peroxynitrite arises from the reaction of nitric oxide (NO) with superoxide radical.…”

Section: Resultsmentioning

confidence: 99%

“…Such a role has already been demonstrated for TNF-␣ (5, 34). The b Data for the uninfected control group were published previously (10). c ND, not done.…”

Section: Discussionmentioning

confidence: 99%

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Neutrophils Do Not Mediate the Pathophysiological Sequelae of Cryptosporidium parvum Infection in Neonatal Piglets

Zadrozny¹,

Stauffer²,

Armstrong³

et al. 2006

Infect Immun

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Cryptosporidium parvum is a minimally invasive protozoal pathogen of intestinal epithelium that results in villus atrophy, mucosal lipid peroxidation, diarrhea, and diminished barrier function. Influx of neutrophils is a consistent feature of human and animal cryptosporidiosis, and yet their contribution to the pathological sequelae of infection has not been investigated. Accordingly, we used an established neonatal piglet model of C. parvum infection to examine the role of neutrophils in disease pathogenesis by inhibiting their recruitment and activation in vivo using a monoclonal anti-CD18 antibody. Infected piglets were treated daily with anti-CD18 or isotype control immunoglobulin G and euthanized at peak infection, at which time neutrophil infiltrates, lipid peroxidation, severity of infection, and intestinal barrier function were quantified. C. parvum infection resulted in a significant increase in mucosal neutrophil myeloperoxidase activity that was prevented by treatment of piglets with anti-CD18 antibody. Neutrophil recruitment was dependent on mucosal superoxide formation (prevented by treatment of infected piglets with superoxide dismutase). Neutrophils did not contribute to peroxynitrite formation or peroxidative injury of C. parvum-infected mucosa and had no impact on the severity of epithelial infection, villus atrophy, or diarrhea. The presence of neutrophils in C. parvuminfected mucosa was associated with enhanced barrier function that could not be attributed to mucosal elaboration of prostaglandins or stimulation of their synthesis. These studies are the first to demonstrate that neutrophilic inflammation arising in response to infection by a noninvasive epithelial pathogen results in physiologic rather than pathological effects in vivo.

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Peroxynitrite, a potent macrophage‐derived oxidizing cytotoxin to combat invading pathogens

2013

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Macrophages are among the first cellular actors facing the invasion of microorganisms. These cells are able to internalize pathogens and destroy them by means of toxic mediators, many of which are produced enzymatically and have strong oxidizing capacity. Indeed, macrophages count on the NADPH oxidase complex activity, which is triggered during pathogen invasion and leads to the production of superoxide radical inside the phagosome. At the same time, the induction of nitric oxide synthase results in the production of nitric oxide in the cytosol which is able to readily diffuse to the phagocytic vacuole. Superoxide radical and nitric oxide react at diffusion controlled rates with each other inside the phagosome to yield peroxynitrite, a powerful oxidant capable to kill microorganisms. Peroxynitrite toxicity resides on oxidations and nitrations of biomolecules in the target cell. The central role of peroxynitrite as a key effector molecule in the control of infections has been proven in a wide number of models. However, some microorganisms and virulent strains adapt to survive inside the potentially hostile oxidizing microenvironment of the phagosome by either impeding peroxynitrite formation or rapidly detoxifying it once formed. In this context, the outcome of the infection process is a result of the interplay between the macrophage-derived oxidizing cytotoxins such as peroxynitrite and the antioxidant defense machinery of the invading pathogens.

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Local Peroxynitrite Formation Contributes to Early Control of Cryptosporidium parvum Infection

Cited by 21 publications

References 40 publications

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

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

Neutrophils Do Not Mediate the Pathophysiological Sequelae of Cryptosporidium parvum Infection in Neonatal Piglets

Peroxynitrite, a potent macrophage‐derived oxidizing cytotoxin to combat invading pathogens

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