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

Marie Hagbom,Ove Lundgren,Lennart Svensson,Thommie Karlsson,John A Taylor,Claudia Istrate,Vesa-Matti Loitto,Jesus Rodriguez-Diaz,Håkan Ahlman,Javier Buesa,Karl-Eric Magnusson,David Engblom

doi:10.1371/journal.ppat.1002115

Abstract

Rotavirus (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 Ca2+ 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 (IP3), 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-HT3 receptor antagonists.

Highlights

Rotavirus (RV) is the major cause of infantile gastroenteritis worldwide and the infection is associated with approximately 600,000 deaths every year, predominantly in developing countries [1]
In this study we have addressed the hypothesis that RV infection triggers the release of serotonin (5-hydroxytryptamine, 5-HT) from enterochromaffin (EC) cells in the intestine leading to activation of vagal afferent nerves connected to brain stem structures associated with vomiting
We have previously shown that RV infection results in stimulation of the enteric nervous system (ENS) and that RV diarrhoea in mice can be attenuated with 5-HT3 receptor antagonists, such as granisetron [3]

Summary

Introduction

Rotavirus (RV) is the major cause of infantile gastroenteritis worldwide and the infection is associated with approximately 600,000 deaths every year, predominantly in developing countries [1]. Most of the deaths result from excessive loss of fluids and electrolytes through vomiting and diarrhoea. Several mechanisms have been proposed to account for the watery diarrhoea associated with RV infection. These include osmotic diarrhoea following a virus-induced loss of epithelial absorptive function, the effect of NSP4, a virus-encoded enterotoxin, and an active role of the enteric nervous system (ENS) and serotonin (5hydroxytryptamine, 5-HT) [2,3,4,5]. The pathophysiological basis of virus-induced emesis, a hallmark of illnesses caused by RV and norovirus, is poorly understood

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