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Rotavirus Stimulates Release of Serotonin (5-HT) from Human Enterochromaffin Cells and Activates Brain Structures Involved in Nausea and Vomiting
Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Clinical Microbiology.
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology.
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2011 (English)In: PLOS PATHOGENS, ISSN 1553-7366, Vol. 7, no 7Article in journal (Refereed) Published
Abstract [en]

otavirus (RV) is the major cause of severe gastroenteritis in young children. A virus-encoded enterotoxin, NSP4 is proposed to play a major role in causing RV diarrhoea but how RV can induce emesis, a hallmark of the illness, remains unresolved. In this study we have addressed the hypothesis that RV-induced secretion of serotonin (5-hydroxytryptamine, 5-HT) by enterochromaffin (EC) cells plays a key role in the emetic reflex during RV infection resulting in activation of vagal afferent nerves connected to nucleus of the solitary tract (NTS) and area postrema in the brain stem, structures associated with nausea and vomiting. Our experiments revealed that RV can infect and replicate in human EC tumor cells ex vivo and in vitro and are localized to both EC cells and infected enterocytes in the close vicinity of EC cells in the jejunum of infected mice. Purified NSP4, but not purified virus particles, evoked release of 5-HT within 60 minutes and increased the intracellular Ca(2+) concentration in a human midgut carcinoid EC cell line (GOT1) and ex vivo in human primary carcinoid EC cells concomitant with the release of 5-HT. Furthermore, NSP4 stimulated a modest production of inositol 1,4,5-triphosphate (IP(3)), but not of cAMP. RV infection in mice induced Fos expression in the NTS, as seen in animals which vomit after administration of chemotherapeutic drugs. The demonstration that RV can stimulate EC cells leads us to propose that RV disease includes participation of 5-HT, EC cells, the enteric nervous system and activation of vagal afferent nerves to brain structures associated with nausea and vomiting. This hypothesis is supported by treating vomiting in children with acute gastroenteritis with 5-HT(3) receptor antagonists.

Place, publisher, year, edition, pages
Public Library of Science (PLoS) , 2011. Vol. 7, no 7
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-69989DOI: 10.1371/journal.ppat.1002115ISI: 000293339300012OAI: oai:DiVA.org:liu-69989DiVA: diva2:433996
Note
Original Publication: Marie Hagbom, Claudia Istrate, David Engblom, Thommie Karlsson, Jesus Rodriguez-Diaz, Javier Buesa, John A Taylor, Vesa Loitto, Karl-Eric Magnusson, Hakan Ahlman, Ove Lundgren and Lennart Svensson, Rotavirus Stimulates Release of Serotonin (5-HT) from Human Enterochromaffin Cells and Activates Brain Structures Involved in Nausea and Vomiting, 2011, PLOS PATHOGENS, (7), 7, . http://dx.doi.org/10.1371/journal.ppat.1002115 Licensee: Public Library of Science (PLoS) http://www.plos.org/Available from: 2011-08-12 Created: 2011-08-12 Last updated: 2015-05-13
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)
Opponent
Supervisors
Available from: 2015-05-13 Created: 2015-05-13 Last updated: 2015-05-13Bibliographically approved

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