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The Cholinergic Anti-Inflammatory Pathway Contributes to the Limited Inflammatory Response following Rotavirus Infection
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.
School of Biological Sciences and Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand.
Department of Microbiology and Immunology, Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Rotavirus causes acute gastroenteritis in young children and is characterized by severe diarrhoea and vomiting. Surprisingly, although rotavirus infection results in significant intestinal pathology, the inflammatory response is limited. We tested the novel hypothesis that rotavirus infection stimulates the cholinergic anti-inflammatory pathway to suppress gut inflammation. The role of the vagus nerve and the α7 nicotinic acetylcholine receptor (α7 nAChR) in rotavirus infection were explored in α7 nAChR gene-deficient mice, vagotomized mice and wild-type mice treated with the α7 nAChR antagonist mecamylamine. TNF-α, IL-1β and IL-6 were measured in serum, spleen, duodenum, jejunum and ileum at 48 hours post infection. To determine if modulation of the inflammatory response affects virus shedding, α7 nAChRs was blocked and virus quantified in faeces. To investigate if stimulation of α7 nAChRs could attenuate rotavirus toxin NSP4-induced cytokine release, mouse peritoneal- and human blood-macrophages were treated with nicotine before NSP4 stimulation.

Our results shows that stimulation of the vagus nerve and α7 nAChRs attenuated the pro- inflammatory response during rotavirus infection and blockade of the α7 nAChR reduced virus shedding from infected mice. IL-6 was increased in duodenum (p<0.05) and serum (p<0.05) of vagotomized mice and in jejunum (p<0.05) and spleen (p<0.05) of α7 nAChR gene-deficient mice. Furthermore, IL-6 mRNA (p<0.01) and TNF-α mRNA (p<0.05) were increased in duodenum of vagotomized animals. Similarly, nicotine attenuated the release of TNF-α (p<0.05) and IL-6 (p<0.05) from macrophages stimulated by NSP4 in vitro, all suggesting that the cholinergic anti- inflammatory pathway contributes to attenuate inflammation during rotavirus infection.

National Category
Microbiology Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:liu:diva-117892OAI: oai:DiVA.org:liu-117892DiVA: diva2:811724
Available from: 2015-05-13 Created: 2015-05-13 Last updated: 2015-05-13Bibliographically approved
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 (print) (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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