Abstract
Bacterial dysentery due to Shigella species is a major cause of morbidity and mortality worldwide. The pathogenesis of Shigella is based on the bacteria's ability to invade and replicate within the colonic epithelium, resulting in severe intestinal inflammatory response and epithelial destruction. Although the mechanisms of pathogenesis of Shigella in the colon have been extensively studied, little is known on the effect of wild-type Shigella on the small intestine and the role of the host response in the development of the disease. Moreover, to the best of our knowledge no studies have described the effects of apically administered Shigella flexneri 2a and S. dysenteriae 1 vaccine strains on human small intestinal enterocytes. The aim of this study was to assess the coordinated functional and immunological human epithelial responses evoked by strains of Shigella and candidate vaccines on small intestinal enterocytes. To model the interactions of Shigella with the intestinal mucosa, we apically exposed monolayers of human intestinal Caco2 cells to increasing bacterial inocula. We monitored changes in paracellular permeability, examined the organization of tight-junctions and the pro-inflammatory response of epithelial cells. Shigella infection of Caco2 monolayers caused severe mucosal damage, apparent as a drastic increase in paracellular permeability and disruption of tight junctions at the cell-cell boundary. Secretion of pro-inflammatory IL-8 was independent of epithelial barrier dysfunction. Shigella vaccine strains elicited a pro-inflammatory response without affecting the intestinal barrier integrity. Our data show that wild-type Shigella infection causes a severe alteration of the barrier function of a small intestinal cell monolayer (a proxy for mucosa) and might contribute (along with enterotoxins) to the induction of watery diarrhea. Diarrhea may be a mechanism by which the host attempts to eliminate harmful bacteria and transport them from the small to the large intestine where they invade colonocytes inducing a strong inflammatory response.
Highlights
Shigellosis is a leading cause of diarrheal disease, in developing countries, estimated to have caused up to 1 million deaths per year between 1966–1997 [1]
Shigellosis is typically characterized by two phases: an initial phase of watery diarrhea thought to arise in the jejunum, followed by a second phase characterized by stools containing blood, mucus and pus, as a result of bacterial invasion of the colonic epithelium
Our data show that exposure to S. flexneri 2a and S. dysenteriae 1 cause a permanent impairment of the mucosal barrier integrity independent of the bacterial inocula and associated to a minimal, significant loss of cell viability
Summary
Shigellosis is a leading cause of diarrheal disease, in developing countries, estimated to have caused up to 1 million deaths per year between 1966–1997 [1]. Travelers and military personnel are at high risk of infection in the endemic countries. In the United States, there are approximately 14,000 laboratoryconfirmed cases of shigellosis and an estimated 448,240 total cases that occur each year, according to the Center for Disease Control [2]. Development of an efficacious vaccine against Shigella is a high priority for the protection of populations in developing countries, where the burden of Shigella causes much morbidity and claims many young lives. The same vaccines would represent a potential tool to protect industrialized country travelers against the risk of travel shigellosis
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