Abstract
The bacterial pathogen Shigella flexneri causes 270 million cases of bacillary dysentery (blood in stool) worldwide every year, resulting in more than 200,000 deaths. A major challenge in combating bacillary dysentery is the lack of a small-animal model that recapitulates the symptoms observed in infected individuals, including bloody diarrhea. Here, we show that similar to humans, infant rabbits infected with S. flexneri experience severe inflammation, massive ulceration of the colonic mucosa, and bloody diarrhea. T3SS-dependent invasion of epithelial cells is necessary and sufficient for mediating immune cell infiltration and vascular lesions. However, massive ulceration of the colonic mucosa, bloody diarrhea, and dramatic weight loss are strictly contingent on the ability of the bacteria to spread from cell to cell. The infant rabbit model features bacterial dissemination as a critical determinant of S. flexneri pathogenesis and provides a unique small-animal model for research and development of therapeutic interventions.
Highlights
The bacterial pathogen Shigella flexneri causes 270 million cases of bacillary dysentery worldwide every year, resulting in more than 200,000 deaths
There is a significant gap in knowledge as to how the molecular and cellular mechanisms supporting S. flexneri intracellular invasion and dissemination relate to pathogenesis
To establish a small-animal model of bacillary dysentery, we investigated the infant rabbit system because it has been successfully used for modeling infection with various human enteric pathogens that reside either in the small intestine or in the colon, such as Vibrio cholerae and Enterohemorrhagic Escherichia coli, respectively[27,28]
Summary
The bacterial pathogen Shigella flexneri causes 270 million cases of bacillary dysentery (blood in stool) worldwide every year, resulting in more than 200,000 deaths. A major challenge in combating bacillary dysentery is the lack of a small-animal model that recapitulates the symptoms observed in infected individuals, including bloody diarrhea. There is a significant gap in knowledge as to how the molecular and cellular mechanisms supporting S. flexneri intracellular invasion and dissemination relate to pathogenesis This is partly due to the lack of a small-animal model of bacillary dysentery. Various small-animal models have been used in the past, including the mouse, the guinea pig, and the adult rabbit[21,22,23,24,25,26] Most of these models are not relevant to the site of S. flexneri infection in humans, that is, the colon. None of these models recapitulate the hallmark of human shigellosis, that is, bloody diarrhea
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