How do the rotavirus NSP4 and bacterial enterotoxins lead differently to diarrhea?

Abstract

Rotavirus is the major cause of infantile gastroenteritis and each year causes 611,000 deaths worldwide. The virus infects the mature enterocytes of the villus tip of the small intestine and induces a watery diarrhea. Diarrhea can occur with no visible tissue damage and, conversely, the histological lesions can be asymptomatic. Rotavirus impairs activities of intestinal disaccharidases and Na+-solute symports coupled with water transport. Maldigestion of carbohydrates and their accumulation in the intestinal lumen as well as malabsorption of nutrients and a concomitant inhibition of water reabsorption can lead to a malabsorption component of diarrhea. Since the discovery of the NSP4 enterotoxin, diverse hypotheses have been proposed in favor of an additional secretion component in the pathogenesis of diarrhea. Rotavirus induces a moderate net chloride secretion at the onset of diarrhea, but the mechanisms appear to be quite different from those used by bacterial enterotoxins that cause pure secretory diarrhea. Rotavirus failed to stimulate Cl- secretion in crypt, whereas it stimulated Cl- reabsorption in villi, questioning, therefore, the origin of net Cl- secretion. A solution to this riddle was that intestinal villi do in fact secrete chloride as a result of rotavirus infection. Also, the overall chloride secretory response is regulated by a phospholipase C-dependent calcium signaling pathway induced by NSP4. However, the overall response is weak, suggesting that NSP4 may exert both secretory and subsequent anti-secretory actions, as did carbachol, hence limiting Cl- secretion. All these characteristics provide the means to make the necessary functional distinction between viral NSP4 and bacterial enterotoxins.

Figure 1

Reality and hypothesis of the pathophysiological mechanisms of rotavirus and NSP4-mediated diarrhea. Rotavirus impairs activities of intestinal disaccharidases and Na+-solute symports coupled with water transport, contributing to massive loss of water into the intestinal lumen. NSP4 specifically inhibits SGLT1-mediated Na+-D-glucose symport activity. Rotavirus and/or NSP4 increases epithelial paracellular permeability, but the importance of this effect on fluid and electrolyte fluxes is difficult to evaluate. Loss of Cl^- into the intestinal lumen is established by Cl^-/H⁺ symport activity (AE2) causing Cl^-reabsorption or Cl^- secretion in villi (depending on the direction of the chloride electrochemical gradient resulting from rotavirus infection), but failing to stimulate Cl^-transport in crypt. NSP4 has no direct, specific effect on either intestinal absorption or secretion of chloride. Net chloride secretion is regulated by a phospholipase C (PLC)-dependent calcium signaling pathway induced by NSP4. NSP4 is also secreted at the basal side of enterocytes, but its role in rotavirus disease remains to be defined. It has been proposed that NSP4 may exert both secretory and subsequent anti-secretory actions via IP₃ and IP₄ respectively, as did carbachol, hence limiting Cl^- secretion. It has also been proposed that Ca²⁺ mobilization may trigger the release of different mediators (cytokines, amines...) which activate the nervous system in the intestinal wall, thereby stimulating Cl^- secretion. The signs - and + indicate inhibition and activation, respectively. Further details in the text.