Abstract
Bacteria of the genus Shigella cause shigellosis, a severe gastrointestinal disease that is a major cause of diarrhea-associated mortality in humans. Mice are highly resistant to Shigella and the lack of a tractable physiological model of shigellosis has impeded our understanding of this important human disease. Here, we propose that the differential susceptibility of mice and humans to Shigella is due to mouse-specific activation of the NAIP-NLRC4 inflammasome. We find that NAIP-NLRC4-deficient mice are highly susceptible to oral Shigella infection and recapitulate the clinical features of human shigellosis. Although inflammasomes are generally thought to promote Shigella pathogenesis, we instead demonstrate that intestinal epithelial cell (IEC)-specific NAIP-NLRC4 activity is sufficient to protect mice from shigellosis. In addition to describing a new mouse model of shigellosis, our results suggest that the lack of an inflammasome response in IECs may help explain the susceptibility of humans to shigellosis.
Highlights
Shigella is a genus of Gram-negative enterobacteriaceae that causes ~269 million infections and~200,000 deaths annually, a quarter of which are of children under the age of five (Khalil et al, 2018).Disease symptoms include fever, abdominal cramping, and inflammatory diarrhea characterized by the presence of neutrophils and, in severe cases, blood (Kotloff et al, 2018)
The virulence plasmid encodes IcsA, a bacterial surface protein that nucleates host actin at the bacterial pole to propel the pathogen through the host cell cytosol and into adjacent epithelial cells (Bernardini et al, 1989; Goldberg and Theriot, 1995)
Cell death was negligible in Shigellainfected mouse Nlrc4–/– bone marrow-derived macrophages (BMMs) (Figure 1A)
Summary
Shigella is a genus of Gram-negative enterobacteriaceae that causes ~269 million infections and~200,000 deaths annually, a quarter of which are of children under the age of five (Khalil et al, 2018).Disease symptoms include fever, abdominal cramping, and inflammatory diarrhea characterized by the presence of neutrophils and, in severe cases, blood (Kotloff et al, 2018). Shigella is a genus of Gram-negative enterobacteriaceae that causes ~269 million infections and. There is no approved vaccine for Shigella and antibiotic resistance continues to rise (Ranjbar and Farahani, 2019). Shigella pathogenesis is believed to be driven by bacterial invasion, replication, and spread within colonic. IECs. Shigella virulence requires a plasmid-encoded type III secretion system (T3SS) that injects ~30 effectors into host cells (Schnupf and Sansonetti, 2019; Schroeder and Hilbi, 2008). The virulence plasmid encodes IcsA, a bacterial surface protein that nucleates host actin at the bacterial pole to propel the pathogen through the host cell cytosol and into adjacent epithelial cells (Bernardini et al., 1989; Goldberg and Theriot, 1995)
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