Rotavirus Stimulates Release of Serotonin (5-HT) from Human Enterochromaffin Cells and Activates Brain Structures Involved in Nausea and Vomiting

Hagbom, Marie; Istrate, Claudia; Engblom, David; Karlsson, Thommie; Rodrı́guez-Dı́az, Jesús; Buesa, Javier; Taylor, John A.; Loitto, Vesa-Matti; Magnusson, Karl‐Eric; Ahlman, Håkan; Lundgren, Ove

doi:10.1371/journal.ppat.1002115

Cited by 166 publications

(176 citation statements)

References 75 publications

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“…Subsequently in Caco -2 cell line and other cell lines effects of NSP4 or its cleavage peptide (aa114-135) on calcium homeostasis, signal transduction pathways, serotonin secretion and Sodium Glucose symporter were studied. The findings have further reinforced its role as a toxin and virulence factor (Tian et al, 1994;Dong et al, 1997;Hagbom et al, 2011;Halaihel et al, 2000). Some studies have associated mutations in the gene with altered virulence (Zhang et al, 1998, Ball et al, 2013Tsugawa et al, 2014).…”

Section: Introductionmentioning

confidence: 83%

Molecular characterization of the rotavirus enterotoxin NSP4 gene of strains causing diarrhoea in children aged 0-5 years in northern India

Srivastava¹,

Jain²,

Khan³

et al. 2015

J App Pharm Sci

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Non structural protein 4 (NSP4) gene of Rotavirus encodes a multifunctional protein which has significant role in viral multiplication and pathogenesis of acute watery diarrhoea associated with rotaviral gastroenteritis. It is known as the first viral enterotoxin and mutations of the gene have been linked to altered pathogenesis. This study was planned to ascertain the genotypes and genetic variations of NSP4 gene in the rotavirus strains prevalent in this area. We collected consecutive diarrhoeal stools from equal no of children aged under five years hospitalized with diarrhoea in a period from January 2010 to June 2012 and tested them for rotavirus antigen by ELISA. NSP4 gene was amplified by RT-PCR and subsequently sequenced (Big-Dye terminator kit using 3130 ABI, Genetic analyzer) and genotyped by Rotavirus C software. Of the 260 samples, 58(22.3%) samples were positive by ELISA. We were able to amplify NSP4 gene by RTPCR from 45 strains of which 35 amplicons were selected for sequencing. Total 25(71.4%) strains belonged to genotype E1, 6 (17.1%) strains to genotype E2 and 4 (11.4%) matched with the genotype E6. Sequence analysis revealed changes in the nucleotides causing punctate mutations in the conserved regions, the Inter species variable domain (ISVD) and the enterotoxin region (amino acid 114-135). On evolutionary analysis of 33 strains amino acid at position 131 was found under positive selection.

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Section: Introductionmentioning

confidence: 83%

Molecular characterization of the rotavirus enterotoxin NSP4 gene of strains causing diarrhoea in children aged 0-5 years in northern India

Srivastava¹,

Jain²,

Khan³

et al. 2015

J App Pharm Sci

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“…Moreover, it has been shown that NSP4 and a cleavage fragment there of is secreted from infected cells 26--28 and that NSP4 can trigger pro--inflammatory cytokines from macrophages via Toll--like receptor--2 29 and stimulate serotonin (5--hydroxytryptamine, 5--HT) release from human EC cells 30 . Still, there are reports in the literature not being consistent with NSP4…”

Section: Proteins Involved In Replication Pathogenesis and Immune Rementioning

confidence: 99%

“…The myenteric plexus provides motor innervation to the circular muscle layer and the longitudinal muscle and regulates intestinal motility including peristalsis 142 . Over the years, it has become more and more evident that ENS is involved in rotavirus diarrhea 30,[74][75][76][77] . By blocking enteric neurotransmitters, that can act to induce active secretion (e.g.…”

Section: The Enteric Nervous Systemmentioning

confidence: 99%

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Rotavirus Disease Mechanisms Diarrhea, Vomiting and Inflammation : How and Why

Hagbom¹

2015

Linköping University Medical Dissertations

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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

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“…Most of the mortality from rotavirus infection results from excessive loss of fluids and electrolytes. Diarrhoea may be caused by several mechanisms, including malabsorption secondary to destruction of enterocytes, villus ischaemia, intestinal hypersecretion stimulated by the rotavirus non-structural enterotoxin protein NSP4, and activation of vagal afferent sensory neurons which transmit information to the hindbrain, leading to nausea and vomiting [50]. With regard to protective immunity, studies in humans and animals have reported correlations between rotavirus antibody levels and protection, the most consistent of which has been with rotavirus-specific serum IgA antibodies.…”

Section: Rotavirus Vaccinesmentioning

confidence: 99%

Vaccines against enteric infections for the developing world

Czerkinsky

Holmgren

2015

Phil. Trans. R. Soc. B

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One contribution of 15 to a discussion meeting issue 'Biological challenges to effective vaccines in the developing world'. Since the first licensure of the Sabin oral polio vaccine more than 50 years ago, only eight enteric vaccines have been licensed for four disease indications, and all are given orally. While mucosal vaccines offer programmatically attractive tools for facilitating vaccine deployment, their development remains hampered by several factors: -limited knowledge regarding the properties of the gut immune system during early life; -lack of mucosal adjuvants, limiting mucosal vaccine development to live-attenuated or killed whole virus and bacterial vaccines; -lack of correlates/surrogates of mucosal immune protection; and -limited knowledge of the factors contributing to oral vaccine underperformance in children from developing countries.There are now reasons to believe that the development of safe and effective mucosal adjuvants and of programmatically sound intervention strategies could enhance the efficacy of current and next-generation enteric vaccines, especially in lesser developed countries which are often co-endemic for enteric infections and malnutrition. These vaccines must be safe and affordable for the world's poorest, confer long-term protection and herd immunity, and must be able to contain epidemics.

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Rotavirus Stimulates Release of Serotonin (5-HT) from Human Enterochromaffin Cells and Activates Brain Structures Involved in Nausea and Vomiting

Cited by 166 publications

References 75 publications

Molecular characterization of the rotavirus enterotoxin NSP4 gene of strains causing diarrhoea in children aged 0-5 years in northern India

Molecular characterization of the rotavirus enterotoxin NSP4 gene of strains causing diarrhoea in children aged 0-5 years in northern India

Rotavirus Disease Mechanisms Diarrhea, Vomiting and Inflammation : How and Why

Vaccines against enteric infections for the developing world

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