EPITHELIAL RESPONSE TO ENTERIC PATHOGENS: ACTIVATION OF CHLORIDE SECRETORY PATHWAYS

This chapter focuses on the disruption of transcellular chloride secretion by microbial pathogens, with emphasis on recent advances in this field. A brief review of normal chloride secretion is outlined in the chapter. Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that lead to mislocalization, altered function, or expression of this protein have serious pathophysiological consequences. Cholera toxin (CT) from Vibrio cholerae and the type I and type II heat-labile enterotoxins (LTI and LTII) from Escherichia coli are the primary agents that mediate the diarrhea caused by these organisms. These toxins belong to the AB5 enterotoxin family. Clostridium difficile, the leading cause of nosocomial enteric infections, is a noninvasive pathogen that causes colitis entirely by the action of two potent exotoxins, toxin A and toxin B. Unlike CT and E. coli enterotoxin, which elicit secretion without an acute inflammatory component, C. difficile toxin triggers marked intestinal inflammation. In the normal intestine, increases in cyclic guanosine monophosphate (cGMP) lead to the phosphorylation and activation of the CFTR by the membrane-bound cGMP-dependent protein kinase II (PKGII) or by cross-activation of the cyclic AMP (cAMP)-dependent protein kinase. Calcium-dependent chloride secretion is a transient response even in the continued presence of the agonist. Secretion via the transcellular pathway is an exquisitely regulated process. Various pathogens and their toxins can directly disrupt these pathways, frequently by invoking multiple mechanisms.