Pathogenesis of rotavirus diarrhea

Abstract

Rotavirus diarrhea is a major cause of infantile gastroenteritis worldwide. This review is mainly devoted to the effects of Rotavirus on intestinal epithelial transport and to the pathophysiological mechanisms proposed to underlie the intestinal fluid secretion caused by the virus.

Figure 1

A speculative hypothesis for Rotavirus-induced diarrhea. Panel A. Cellular events leading to diarrhea. Rotavirus and/or its enterotoxin NSP4 inhibits fluid and electrolyte transport of the villus epithelium by attenuating the Na-glucose symport SGLT1 and possibly also Na-amino acid symports (not shown). Concomitantly, disaccharidase activity is inhibited. It is possible that the Na, K pump in the basolateral membrane is also attenuated, although quantitatively this effect is much less pronounced than for the disaccharidases. Taken together, these events will lower the rates of fluid, electrolyte and glucose absorption. The paracellular epithelial permeability is increased by Rotavirus and NSP4. The importance of this effect for epithelial transport is difficult to judge. Intracellular calcium concentration is increased in the intestinal epithelium in response to virus/NSP4. This may evoke the release of amines/peptides from intestinal endocrine cells (middle cell). Furthermore, cytokines, prostaglandins and NO are known to be released from the enterocytes in response to microorganisms. All these biologically active compounds may, alone or together, activate neuronal dendrites located just underneath the intestinal epithelium and hence stimulate secretory reflexes in the ENS. For a more detailed account of the intracellular mechanisms leading to an increased calcium concentration, the reader is referred to reference . Panel B. Integrative events leading to diarrhea. NSP4 may diffuse into the crypts to directly influence the intestinal secretory epithelium, possibly via the NSP4 effect on intracellular calcium. Furthermore, Rotavirus and/or NSP4 may activate secretory reflexes in the ENS in the way depicted in panel A. Inflammatory mediators, if present, may also stimulate nervous reflexes. The nervous reflex shown in the figure represents the simplest model that can be constructed from the observations made with cholera toxin. No pharmacological analysis has been made of the nervous reflex activated by Rotavirus. Minus sign indicates an attenuation; plus sign an increase. Shaded cells in panel B depict endocrine cells.

Figure 1

A speculative hypothesis for Rotavirus-induced diarrhea. Panel A. Cellular events leading to diarrhea. Rotavirus and/or its enterotoxin NSP4 inhibits fluid and electrolyte transport of the villus epithelium by attenuating the Na-glucose symport SGLT1 and possibly also Na-amino acid symports (not shown). Concomitantly, disaccharidase activity is inhibited. It is possible that the Na, K pump in the basolateral membrane is also attenuated, although quantitatively this effect is much less pronounced than for the disaccharidases. Taken together, these events will lower the rates of fluid, electrolyte and glucose absorption. The paracellular epithelial permeability is increased by Rotavirus and NSP4. The importance of this effect for epithelial transport is difficult to judge. Intracellular calcium concentration is increased in the intestinal epithelium in response to virus/NSP4. This may evoke the release of amines/peptides from intestinal endocrine cells (middle cell). Furthermore, cytokines, prostaglandins and NO are known to be released from the enterocytes in response to microorganisms. All these biologically active compounds may, alone or together, activate neuronal dendrites located just underneath the intestinal epithelium and hence stimulate secretory reflexes in the ENS. For a more detailed account of the intracellular mechanisms leading to an increased calcium concentration, the reader is referred to reference . Panel B. Integrative events leading to diarrhea. NSP4 may diffuse into the crypts to directly influence the intestinal secretory epithelium, possibly via the NSP4 effect on intracellular calcium. Furthermore, Rotavirus and/or NSP4 may activate secretory reflexes in the ENS in the way depicted in panel A. Inflammatory mediators, if present, may also stimulate nervous reflexes. The nervous reflex shown in the figure represents the simplest model that can be constructed from the observations made with cholera toxin. No pharmacological analysis has been made of the nervous reflex activated by Rotavirus. Minus sign indicates an attenuation; plus sign an increase. Shaded cells in panel B depict endocrine cells.