title: Rotavirus and Serotonin Cross-Talk in Diarrhoea.
abstract: Rotavirus (RV) has been shown to infect and stimulate secretion of serotonin from human enterochromaffin (EC) cells and to infect EC cells in the small intestine of mice. It remains to identify which intracellularly expressed viral protein(s) is responsible for this novel property and to further establish the clinical role of serotonin in RV infection. First, we found that siRNA specifically silencing NSP4 (siRNANSP4) significantly attenuated secretion of serotonin from Rhesus rotavirus (RRV) infected EC tumor cells compared to siRNAVP4, siRNAVP6 and siRNAVP7. Second, intracellular calcium mobilization and diarrhoeal capacity from virulent and avirulent porcine viruses correlated with the capacity to release serotonin from EC tumor cells. Third, following administration of serotonin, all (10/10) infants, but no (0/8) adult mice, responded with diarrhoea. Finally, blocking of serotonin receptors using Ondansetron significantly attenuated murine RV (strain EDIM) diarrhoea in infant mice (2.9 vs 4.5 days). Ondansetron-treated mice (n = 11) had significantly (p < 0.05) less diarrhoea, lower diarrhoea severity score and lower total diarrhoea output as compared to mock-treated mice (n = 9). Similarly, Ondansetron-treated mice had better weight gain than mock-treated animals (p < 0.05). A most surprising finding was that the serotonin receptor antagonist significantly (p < 0.05) also attenuated total viral shedding. In summary, we show that intracellularly expressed NSP4 stimulates release of serotonin from human EC tumor cells and that serotonin participates in RV diarrhoea, which can be attenuated by Ondansetron.
authors.affiliation: Department of Clinical and Experimental Medicine, Division of Molecular Virology, Linköping University, Linköping, Sweden.
authors.forename: Sonja
authors.initials: S
authors.lastname: Bialowas
authors.affiliation: Department of Clinical and Experimental Medicine, Division of Molecular Virology, Linköping University, Linköping, Sweden.
authors.forename: Marie
authors.initials: M
authors.lastname: Hagbom
authors.affiliation: Department of Clinical and Experimental Medicine, Division of Molecular Virology, Linköping University, Linköping, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Nordgren
authors.affiliation: Department of Clinical and Experimental Medicine, Division of Medical Microbiology, Linköping University, Linköping, Sweden.
authors.forename: Thommie
authors.initials: T
authors.lastname: Karlsson
authors.affiliation: Department of Clinical and Experimental Medicine, Division of Molecular Virology, Linköping University, Linköping, Sweden.
authors.forename: Sumit
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Department of Clinical and Experimental Medicine, Division of Medical Microbiology, Linköping University, Linköping, Sweden.
authors.forename: Karl-Eric
authors.initials: KE
authors.lastname: Magnusson
authors.affiliation: Department of Clinical and Experimental Medicine, Division of Molecular Virology, Linköping University, Linköping, Sweden.
authors.forename: Lennart
authors.initials: L
authors.lastname: Svensson
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D003967:Diarrhea / Q000378:metabolism* / Q000821:virology*; D004195:Disease Models, Animal; D004759:Enterochromaffin Cells / Q000378:metabolism / Q000821:virology; D015870:Gene Expression; D020868:Gene Silencing; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D054884:Host-Pathogen Interactions; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology / Q000821:virology; D007421:Intestine, Small / Q000378:metabolism / Q000473:pathology / Q000821:virology; D051379:Mice; D011985:Receptors, Serotonin / Q000378:metabolism; D012401:Rotavirus / Q000187:drug effects / Q000502:physiology*; D012400:Rotavirus Infections / Q000378:metabolism* / Q000821:virology*; D012701:Serotonin / Q000378:metabolism* / Q000494:pharmacology; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D014118:Toxins, Biological / Q000235:genetics / Q000378:metabolism; D014365:Tryptophan Hydroxylase / Q000235:genetics / Q000378:metabolism; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000378:metabolism; D014774:Virulence / Q000235:genetics; D017201:Virus Shedding
chemical_list: D006023:Glycoproteins; C081369:NS28 protein, rotavirus; D011985:Receptors, Serotonin; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; D014118:Toxins, Biological; D017361:Viral Nonstructural Proteins; D012701:Serotonin; C487801:Tph1 protein, mouse; D014365:Tryptophan Hydroxylase; D002118:Calcium