Malnutrition Modifies Pig Small Intestinal Inflammatory Responses to Rotavirus

Zijlstra, R. T.; McCracken, B A; Odle, Jack; Donovan, Sharon M.; Gelberg, Howard B.; Petschow, Bryon W.; Zuckermann, Federico A.; Gaskins, H. Rex

doi:10.1093/jn/129.4.838

Cited by 42 publications

(32 citation statements)

References 21 publications

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“…Our results are in agreement with other studies in which elevated levels of PGE 2 and PGF 2 were detected in the plasma and stool of rotavirus-infected children (66) and elevated intestinal PGE 2 concentrations were found in piglets early after rotavirus infection (69). In addition, many other viruses are known to modify COX-2 expression and PG production (29,33,34,37,43,47,59,67).…”

Section: Discussionsupporting

confidence: 93%

Inhibition of Cyclooxygenase Activity Reduces Rotavirus Infection at a Postbinding Step

Rossen

Bouma

Raatgeep

et al. 2004

J Virol

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Elevated levels of prostaglandins (PGs), products of cyclooxygenases (COXs), are found in the plasma and stool of rotavirus-infected children. We sought to determine the role of COXs, PGs, and the signal transduction pathways involved in rotavirus infection to elucidate possible new targets for antiviral therapy. Human intestinal Caco-2 cells were infected with human rotavirus Wa or simian rotavirus SA-11. COX-2 mRNA expression and secreted PGE 2 levels were determined at different time points postinfection, and the effect of COX inhibitors on rotavirus infection was studied by an immunofluorescence assay (IFA). To reveal the signal transduction pathways involved, the effect of MEK, protein kinase A (PKA), p38 mitogen-activated protein kinase (MAPK), and NF-B inhibitors on rotavirus infection was analyzed. In infected Caco-2 cells, increased COX-2 mRNA expression and secreted PGE 2 levels were detected. Indomethacin (inhibiting both COX-1 and COX-2) and specific COX-1 and COX-2 inhibitors reduced rotavirus infection by 85 and 50%, respectively, as measured by an IFA. Indomethacin reduced virus infection at a postbinding step early in the infection cycle, inhibiting virus protein synthesis. Indomethacin did not seem to affect viral RNA synthesis. Inhibitors of MEK, PKA, p38 MAPK, and NF-B decreased rotavirus infection by at least 40%. PGE 2 counteracted the effect of the COX and PKA inhibitors but not of the MEK, p38 MAPK, and NF-B inhibitors. Conclusively, COXs and PGE 2 are important mediators of rotavirus infection at a postbinding step. The ERK1/2 pathway mediated by PKA is involved in COX induction by rotavirus infection. MAPK and NF-B pathways are involved in rotavirus infection but in a PGE 2 -independent manner. This report offers new perspectives in the search for therapeutic agents in treatment of severe rotavirus-mediated diarrhea in children.

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Section: Discussionsupporting

confidence: 93%

Inhibition of Cyclooxygenase Activity Reduces Rotavirus Infection at a Postbinding Step

Rossen

Bouma

Raatgeep

et al. 2004

J Virol

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“…It is unclear if virus replication is required for induction of chemokine secretion (9,66). In addition, the levels of PGE 2 are increased in infected intestine (79). The chemokines may activate the immune response rather than directly contribute to diarrhea.…”

Section: The Molecular Basis Of Diarrhea Inductionmentioning

confidence: 99%

“…Another study suggested that the diarrhea was malabsorptive and resulted from epithelial damage caused by villus ischemia (58). A secretory component of the diarrhea was suggested, based on elevated levels of prostaglandin E 2 (PGE 2 ) in the infected gut and the stimulation of secretion by PGE 2 (79). The fact that gut lesions often do not correlate with the presence of diarrhea stimulated the search for other mechanisms of diarrhea induction.…”

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confidence: 99%

“…Several host factors have also been shown to affect the severity of rotavirus disease, including the following. (i) Malnutrition is documented to increase the severity of rotavirus diarrhea (71), where it delays small intestinal recovery (78) and modifies intestinal inflammatory responses (79). (ii) Rotavirus symptomatic infections are generally age restricted (13).…”

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Pathogenesis of Intestinal and Systemic Rotavirus Infection

Ramig

2004

J Virol

314

230

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Rotaviruses are responsible for significant gastrointestinal disease, primarily in children Ͻ5 years of age and the young of other mammalian species. Each year rotaviruses cause approximately 111 million episodes of gastroenteritis in children, which result in 25 million visits to clinics, 2 million hospitalizations, and 352,000 to 592,000 deaths. On a worldwide basis, nearly every child experiences rotavirus gastroenteritis by age 5, 1 in 5 visits a clinic, 1 in 65 is hospitalized, and 1 in 293 dies. Children in the poorest countries account for 82% of rotavirus deaths (60). This disease burden underscores a need for interventions such as vaccines. A vaccine was developed and approved, but recommendation for its use was withdrawn because of vaccination-associated adverse events (57). Additional information about the molecular biology, immunology, and pathogenesis of rotavirus infection will inform ongoing vaccine development efforts.Our understanding of rotavirus-induced diarrheal disease is incomplete compared to that of several other pathogens (e.g., cholera). Rotavirus diarrhea has been attributed to several different mechanisms, including malabsorption secondary to enterocyte destruction, a virus-encoded toxin, stimulation of the enteric nervous system (ENS), and villus ischemia (13,45). Over the past several years, numerous studies have addressed mechanisms of diarrhea induction at the cellular and tissue levels, and a new understanding of the mechanisms is beginning to emerge. Here I will briefly outline the new data and present our current understanding of how rotaviruses induce diarrhea in the infected host.Recent studies confirm sporadic case reports that rotavirus infection is not confined to the intestine as was generally assumed. Although systemic sequellae to rotavirus infection are apparently rare, reports have continually appeared in the literature, and recent work with animal models has begun to shed light on how the virus spreads to extraintestinal sites. Our current understanding of extraintestinal spread and infection will also be considered below. GENERAL CHARACTERISTICS OF ROTAVIRUS INFECTION AND DISEASE IN HUMANS AND ANIMALSRotavirus. Rotaviruses comprise a genus within the family Reoviridae. The rotavirion has a nonenveloped, complex, triple-layered capsid structure that surrounds a genome composed of 11 segments of double-stranded RNA. There are six structural proteins and six nonstructural proteins, each encoded in a unique genome segment except for nonstructural proteins 5 and 6 (NSP5 and NSP6), which are encoded in overlapping reading frames of a single segment. The rotavirus genus is divided into serological groups (A to E). Groups A to C infect humans, and all groups infect animals. All the information presented here is in regard to group A virus infections.Pathophysiology of rotavirus diarrhea. The enterocytes lining the small intestine are generally divided into two types: enterocytes and crypt cells (Fig. 1). Villus enterocytes are mature, nonproliferating cells covering the vill...

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“…Extending our previously established malnutrition-rotavirus model (61,62), in experiment 1, we used a total of 40 piglets distributed over 2 treatment regimens as follows: 1) control noninfected animals fed full-strength formula or 2) rotavirus-infected animals malnourished by feeding formula diluted 50% with electrolyte solution (1.91 g/l KCl, 0.15 g/l NaCl, and 1.65 g/l Na citrate). Intestinal samples were collected on days 0, 1, 3, 5, and 11 postinfection.…”

Section: Animals and Experimental Designmentioning

confidence: 99%

Intestinal ribosomal p70^S6Ksignaling is increased in piglet rotavirus enteritis

Rhoads

Corl

Harrell

et al. 2007

American Journal of Physiology-Gastrointestinal and Liver Physi

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Recent identification of the mammalian target of rapamycin (mTOR) pathway as an amino acid-sensing mechanism that regulates protein synthesis led us to investigate its role in rotavirus diarrhea. We hypothesized that malnutrition would reduce the jejunal protein synthetic rate and mTOR signaling via its target, ribosomal p70 S6 kinase (p70S6K). Newborn piglets were artificially fed from birth and infected with porcine rotavirus on day 5 of life. Study groups included infected (fully fed and 50% protein calorie malnourished) and noninfected fully fed controls. Initially, in “worst-case scenario studies,” malnourished infected piglets were killed on days 1, 3, 5, and 11 postinoculation, and jejunal samples were compared with controls to determine the time course of injury and p70S6Kactivation. Using a 2 × 2 factorial design, we subsequently determined if infection and/or malnutrition affected mTOR activation on day 3. Western blot analysis and immunohistochemistry were used to measure total and phosphorylated p70S6K; [3H]phenylalanine incorporation was used to measure protein synthesis; and lactase specific activity and villus-crypt dimensions were used to quantify injury. At the peak of diarrhea, the in vitro jejunal protein synthetic rate increased twofold (compared with the rate in the uninfected pig jejunum), concomitant with increased jejunal p70S6Kphosphorylation (4-fold) and an increased p70S6Klevel (3-fold, P < 0.05). Malnutrition did not alter the magnitude of p70S6Kactivation. Immunolocalization revealed that infection produced a major induction of cytoplasmic p70S6Kand nuclear phospho-p70S6K, mainly in the crypt. A downregulation of semitendinosus muscle p70S6Kphosphorylation was seen at days 1–3 postinoculation. In conclusion, intestinal activation of p70S6Kwas not inhibited by malnutrition but was strongly activated during an active state of mucosal regeneration.

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Malnutrition Modifies Pig Small Intestinal Inflammatory Responses to Rotavirus

Cited by 42 publications

References 21 publications

Inhibition of Cyclooxygenase Activity Reduces Rotavirus Infection at a Postbinding Step

Inhibition of Cyclooxygenase Activity Reduces Rotavirus Infection at a Postbinding Step

Pathogenesis of Intestinal and Systemic Rotavirus Infection

Intestinal ribosomal p70^S6Ksignaling is increased in piglet rotavirus enteritis

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Malnutrition Modifies Pig Small Intestinal Inflammatory Responses to Rotavirus

Cited by 42 publications

References 21 publications

Inhibition of Cyclooxygenase Activity Reduces Rotavirus Infection at a Postbinding Step

Inhibition of Cyclooxygenase Activity Reduces Rotavirus Infection at a Postbinding Step

Pathogenesis of Intestinal and Systemic Rotavirus Infection

Intestinal ribosomal p70S6Ksignaling is increased in piglet rotavirus enteritis

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Intestinal ribosomal p70^S6Ksignaling is increased in piglet rotavirus enteritis