Abstract
Shigella species cause diarrheal disease globally. Shigellosis is typically characterized by bloody stools and colitis with mucosal damage and is the leading bacterial cause of diarrheal death worldwide. After the pathogen is orally ingested, it invades and replicates within the colonic epithelium through mechanisms that rely on its type III secretion system (T3SS). Currently, oral infection-based small animal models to study the pathogenesis of shigellosis are lacking. Here, we found that orogastric inoculation of infant rabbits with Shigella flexneri resulted in diarrhea and colonic pathology resembling that found in human shigellosis. Fasting animals prior to S. flexneri inoculation increased the frequency of disease. The pathogen colonized the colon, where both luminal and intraepithelial foci were observed. The intraepithelial foci likely arise through S. flexneri spreading from cell to cell. Robust S. flexneri intestinal colonization, invasion of the colonic epithelium, and epithelial sloughing all required the T3SS as well as IcsA, a factor required for bacterial spreading and adhesion in vitro Expression of the proinflammatory chemokine interleukin 8 (IL-8), detected with in situ mRNA labeling, was higher in animals infected with wild-type S. flexneri versus mutant strains deficient in icsA or T3SS, suggesting that epithelial invasion promotes expression of this chemokine. Collectively, our findings suggest that oral infection of infant rabbits offers a useful experimental model for studies of the pathogenesis of shigellosis and for testing of new therapeutics.IMPORTANCEShigella species are the leading bacterial cause of diarrheal death globally. The pathogen causes bacillary dysentery, a bloody diarrheal disease characterized by damage to the colonic mucosa and is usually spread through the fecal-oral route. Small animal models of shigellosis that rely on the oral route of infection are lacking. Here, we found that orogastric inoculation of infant rabbits with S. flexneri led to a diarrheal disease and colonic pathology reminiscent of human shigellosis. Diarrhea, intestinal colonization, and pathology in this model were dependent on the S. flexneri type III secretion system and IcsA, canonical Shigella virulence factors. Thus, oral infection of infant rabbits offers a feasible model to study the pathogenesis of shigellosis and to develop and test new therapeutics.
Highlights
We found that orogastric inoculation of infant rabbits with S. flexneri results in severe disease resembling human shigellosis
We found that orogastric inoculation of infant rabbits with enterohemorrhagic Escherichia coli (EHEC), Vibrio cholerae, and Vibrio parahaemolyticus [34,35,36] leads to diarrheal diseases and pathologies that mimic their respective human counterparts
We explored the suitability of orogastric inoculation of infant rabbits to model Shigella infection
Summary
Shigella species are Gram-negative, rod-shaped bacteria that cause bacillary dysentery, a severe and often bloody diarrheal disease characterized by inflammatory colitis that can be life-threatening [1] This enteric pathogen, which is spread by the fecal-oral route in humans, does not have an animal reservoir or vector [1]. The adult rabbit ligated ileal loop model has proven useful for the study of Shigella virulence factors [20] This model bypasses the normal route of infection and challenges the small intestine, which is not the primary site of pathology in human infections. The lack of a robust, oral inoculation-based, small animal model of shigellosis has limited understanding of the role of virulence factors in pathogenesis, of the importance of such factors for enabling intestinal colonization and for generating pathology and clinical signs
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