An oral inoculation infant rabbit model forShigellainfection

Abstract

AbstractShigellaspecies 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. Following oral ingestion, the pathogen 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 oro-gastric inoculation of infant rabbits withS. flexneriresulted in diarrhea and colonic pathology resembling that found in human shigellosis. Fasting animals prior toS. flexneriinoculation increased the frequency of disease. The pathogen colonized the colon, where both luminal and intraepithelial foci were observed. The intraepithelial foci likely arise throughS. flexnerispreading from cell-to-cell. RobustS. flexneriintestinal 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 IL-8, detected with in situ mRNA labeling, was higher in animals infected with wild-typeS. flexneriversus mutant strains deficient inicsAor 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.ImportanceShigellaspecies 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 oro-gastric inoculation of infant rabbits withS. flexneriled to a diarrheal disease and colonic pathology reminiscent of human shigellosis. Diarrhea, intestinal colonization and pathology in this model were dependent on theS. flexneritype III secretion system and IcsA, canonicalShigellavirulence factors. Thus, oral infection of infant rabbits offers a feasible model to study the pathogenesis of shigellosis and to develop and test new therapeutics.