The virulent porcine NSP4 OSU-v and attenuated OSU-a were cloned from a pair of porcine rotavirus strains. OSU-v induces severe diarrhea in piglets and neonatal mice; however, serial passage in tissue culture resulted in an attenuated strain, called OSU-a, with significantly

reduced pathogenicity [19]. SA11 NSP4 and OSU-v NSP4 exogenously administered to human colonic adenocarcinoma HT29 cells induce a significant mobilization (10-fold increase) in intracellular calcium ([Cai2+]) compared selleck compound to OSU-a. Although further studies will be needed to fully understand the mechanism of adjuvancity of these proteins, the fact that all three forms of NSP4

(SA11, OSU-v and OSU-a) possess similar adjuvant activities suggests that this activity is independent of the diarrhea-inducing or calcium mobilization abilities of these proteins. Future studies should also test the adjuvant activity potency of NSP4 from other rotavirus strains. The mechanism by which NSP4 exerts its adjuvant function remains to be determined. Although the viral enterotoxin NSP4 causes diarrhea in rodents like the well-characterized bacterial enterotoxins, LT and CT, the mechanisms of pathogenesis and host age restrictions are different. click here Therefore, we anticipate that the mechanism by which NSP4 exerts its adjuvant effect is likely to be different from LT or CT. NSP4 does not induce detectable elevations in intracellular cAMP (unpublished data), which has been shown to be necessary for bacterial toxins to function as mucosal adjuvants [20]. Another possible explanation may be due to the direct effect NSP4 exerts on tight junctions similar to the zonula occludens toxin (ZOT) which also possesses adjuvant function [21] and [22]. Consequently NSP4 can decrease

membrane permeability [23] and such interruptions 17-DMAG (Alvespimycin) HCl of the tight junction can impact mucosal permeability, integrity and overall function of the epithelium. Another possible mechanism could be related to the recent discovery that the α1β1 and α2β1 integrins are receptors for full-length SA11, OSU-a/-v NSP4 and NSP4(112–175) [24]. Ligand-binding to integrin receptors can trigger an intracellular signal transduction pathway resulting in transcription factor activation with subsequent downstream attenuation of the immune system. As these integrins play a role in modulating the immune system [25], [26] and [27] it will be interesting to determine if NSP4 exerts its adjuvant effect through binding to these receptors. Even though other mucosal adjuvants have been explored extensively in the past, to date, none have been approved for human use to be given by mucosal routes.