The disease mechanisms associated with onset and secondary effects of rotavirus (RV) diarrhea remain to be determined and may not be identical. In this study, we investigated whether onset of RV diarrhea is associated with increased intestinal permeability and/or motility. To study the transit time, fluorescent fluorescein isothiocyanate (FITC)-dextran was given to RV-infected adult and infant mice. Intestinal motility was also studied with an opioid receptor agonist (loperamide) and a muscarinic receptor antagonist (atropine). To investigate whether RV increases permeability at the onset of diarrhea, fluorescent 4- and 10-kDa dextran doses were given to infected and noninfected mice, and fluorescence intensity was measured subsequently in serum. RV increased transit time in infant mice. Increased motility was detected at 24 h postinfection (h p.i.) and persisted up to 72 h p.i in pups. Both loperamide and atropine decreased intestinal motility and attenuated diarrhea. Analysis of passage of fluorescent dextran from the intestine into serum indicated unaffected intestinal permeability at the onset of diarrhea (24 to 48 h p.i.). We show that RV-induced diarrhea is associated with increased intestinal motility via an activation of the myenteric nerve plexus, which in turn stimulates muscarinic receptors on intestinal smooth muscles.

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.

In presence of low or high levels of rotavirus-specific maternal antibodies, the ability of newborn mice to respond to immunization with rotavirus RF 8*-2/6/7 VLPs, was evaluated. After parenteral vaccination, 100% of offspring born to low-antibody-titer dams developed rotavirus-specific IgG antibodies (n = 7). In contrast, only 25% of offsprings born to high-antibody-titer dams responded to parenteral immunization (n = 12). When comparing parenteral versus oral immunization in offspring to low-antibody-titer dams only 45% responded after oral immunization (n = 6). In conclusion, the response to parenteral immunization was not hampered by the presence of low levels of maternal antibodies induced by a natural infection while oral immunization was impaired. However, high levels of maternal antibodies impaired the response to parenteral immunization. © 2008 Elsevier Ltd. All rights reserved.

While IgA is proposed to be essential to control rotavirus disease, no information is available how IgA deficient individuals modulate rotavirus disease and immune responses. We report that individuals (n=62) with selective IgA deficiency ( IgA-D) (<0,05g/l) resolve rotavirus disease and show higher total IgG and IgG1 subclass antibody titers to rotavirus than IgA proficient individuals ( n=62) (GMT 18101 vs 4000 (p<0.005); 8463 vs 1691, (p<0.005). We conclude that IgA is not essential for resolving rotavirus infection in humans.

Rotavirus virus-like particles (RV-VLPs) represent a novel strategy for development of a rotavirus subunit vaccine. In this study, RF 8-2/6/7-VLPs with rotavirus VP8 protein (amino acid 1-241 of VP4) fused to the amino terminal end of a truncated VP2, were evaluated for their immunogenic and protective properties. A single intramuscular dose of, either 2 or 20 μg, RF 8-2/6/7-VLPs alone or combined with a potent adjuvant poly[di(carboxylatophenoxy)]phosphazene] (PCPP) induced rotavirus-specific serum IgG and IgA, fecal IgG titers that were enhanced 5-90-fold by adjuvant. Passive protective immunity was achieved in offspring to dams vaccinated with 2 and 20 μg RV-VLPs in presence of adjuvant and 20 μg RV-VLP without adjuvant. © 2008 Elsevier Ltd. All rights reserved.