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Rotavirus Infection Increases Intestinal Motility but Not Permeability at the Onset of Diarrhea
Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
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2014 (English)In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 88, no 6, 3161-3169 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
American Society for Microbiology , 2014. Vol. 88, no 6, 3161-3169 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-105750DOI: 10.1128/JVI.02927-13ISI: 000332126000010OAI: oai:DiVA.org:liu-105750DiVA: diva2:710327
Available from: 2014-04-07 Created: 2014-04-04 Last updated: 2017-12-05
In thesis
1. Rotavirus Disease Mechanisms Diarrhea, Vomiting and Inflammation: How and Why
Open this publication in new window or tab >>Rotavirus Disease Mechanisms Diarrhea, Vomiting and Inflammation: How and Why
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Rotavirus infections cause diarrhea and vomiting that can lead to severe dehydration. Despite extensive tissue damage and cell death, the inflammatory response is very limited. The focus of this thesis was to study pathophysiological mechanisms behind diarrhea and vomiting during rotavirus infection and also to investigate the mechanism behind the limited inflammatory response.

An important discovery in this thesis was that rotavirus infection and the rotavirus toxin NSP4 stimulate release of the neurotransmitter serotonin from intestinal sensory enterochromaffin cells, in vitro and ex vivo. Interestingly, serotonin is known to be a mediator of both diarrhea and vomiting. Moreover, mice pups infected with rotavirus responded with central nervous system (CNS) activation in brain structures associated with vomiting, thus indicating a cross-talk between the gut and brain in rotavirus disease.

Our finding that rotavirus infection activates the CNS led us to address the hypothesis that rotavirus infection not only activates the vagus nerve to stimulate vomiting, but also suppresses the inflammatory response via the cholinergic anti-inflammatory pathway, both of which are mediated by activated vagal afferent nerve signals into the brain stem. We found that mice lacking an intact vagus nerve, and mice lacking the α7 nicotine acetylcholine receptor (nAChR), being involved in cytokine suppression from macrophages, responded with a higher inflammatory response.

Moreover, stimulated cytokine release from macrophages, by the rotavirus toxin NSP4, could be attenuated by nicotine, an agonist of the α7 nAChR. Thus, it seems most reasonable that the cholinergic anti-inflammatory pathway contributes to the limited inflammatory response during rotavirus infection. Moreover, rotavirus-infected mice displayed increased intestinal motility at the onset of diarrhea, which was not associated with increased intestinal permeability. The increased motility and diarrhea in infant mice could be attenuated by drugs acting on the enteric nervous system, indicating the importance and contribution of nerves in the rotavirus mediated disease.

In conclusion, this thesis provides further insight into the pathophysiology of diarrhea and describe for the first time how rotavirus and host cross-talk to induce the vomiting reflex and limit inflammation. Results from these studies strongly support our hypothesis that serotonin and activation of the enteric nervous system and CNS contributes to diarrhea, vomiting and suppression of the inflammatory response in rotavirus disease.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2015. 56 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1463
National Category
Cell and Molecular Biology Microbiology in the medical area
Identifiers
urn:nbn:se:liu:diva-117895 (URN)10.3384/diss.diva-117895 (DOI)978-91-7519-052-5 (ISBN)
Public defence
2015-06-05, Berzeliussalen, Campus US, Linköping, 09:00 (Swedish)
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Supervisors
Available from: 2015-05-13 Created: 2015-05-13 Last updated: 2015-05-13Bibliographically approved

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Istrate, ClaudiaHagbom, MarieVikström, ElenaMagnusson, Karl-EricSvensson, Lennart

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