Pathogenesis of infectious diarrhea: CONCLUSIONS AND ADDENDUM


CONCLUSIONS AND ADDENDUMIn this overview, a range of organisms have been considered, and examples of how the normal function of the gut is perturbed were provided. The emphasis has been on the microbial determinants and mechanisms involved in the primary interaction of pathogen with gut epithelia (Figure 9). Allusions have been made to subsequent involvement of host responses such as the inflammatory response, the production and release of potent cytokines, and accelerated homeostatic responses (as for example in rapid villus resynthesis) seen in many infections. While these host responses are clearly of great importance in the full explanation of diarrheal secretion, no attempts have been made to discuss them in detail, for two reasons: lack of space and lack of research-based competence of the reviewer.

Diarrheal mechanisms

Figure 9) Diarrheal mechanisms: initial stages and (for rotavirus) some intermediate stages in disease progression. A schematic summary of diarrheal mechanisms in some of the infections discussed in the text. In all cases, broken arrows indicate uncertainty about the number and nature of intermediate steps in the return to normality of affected villi in self-limiting diarrheal disease. For clarity, the blood supply in and both blood supply and enteric nervous system in and have been omitted. A normal villus; the shading intensity (as in Figure 1) represents the magnitude of osmolarity. Intoxication of villi by noninvasive pathogens such as Vibrio cholerae and enterotoxigenic Escherichia coli (ETEC). The main diarrheal determinant is cholera toxin (CT) in V cholerae and heat-labile toxins and heat-stable toxins in ETEC. However, as discussed in the text, toxins are not the whole story, hence the broken arrows. Disease caused by inva-sive pathogens such as nonhistotoxic Salmonella typhimurium and rotavirus. Villi are shortened, with presumed loss of absorption and observed increase in secretion. Again, the mechanistic pathway for return to normality is not known. Loss of epithelia due to a histo-toxin seen in some strains of S typhimurium. Loss of enterocytes affect absorption and open up other routes for progressive invasion. Note the broken arrow. A more complete experimentally based understand-ing of the pathophysiological mechanisms is possible in rotavirus infection of neonatal mice. The main point is that conventional wisdom is not sustained: maximum diarrhea occurred during the resynthesis of truncated villi, and villus shortening was preceded or caused by ischemia. Prolongation of diarrhea coincided with nonhypertonic villi; diarrhea ceased on reconstitution of hypertonic villus tip regions. It is possible to infer that some of these intermediate steps take place in other gut infections. AV Arterial vessel; VR Venous return. Reproduced with permission from reference 99


Attention is drawn to two papers. Blocker et al present beautiful electron microscopic visualization of the Shigella needle complex, which forms an essential part of the type III secretion system (‘secreton’), which delivers to target cells those effector proteins that initiate the process leading to bacillary dysentery. Comparisons and contrasts are drawn with equivalent systems in Salmonella and E coli. In a study by Roby et al, a chromosomal locus was cloned which mapped at c centisome 25 on the Salmonella chromosome close to, but distinct from, SPI-5. The biological properties of the recombinant clone suggest that it encodes a ‘gut-responsive’ pleiotropic regulator of genes involved in adaptation to the in vivo gut environment and gastroenteritic virulence.

This entry was posted in Diarrhea and tagged Bibrio cholerae, Clostridium difficile, Diarrhea, Escherichia coli, Shigella dysenteri.