Abstract
Shigella is one of the leading bacterial causes of diarrhea worldwide, affecting more than 165 million people annually. Among the serotypes of Shigella, Shigella sonnei is physiologically unique and endemic in human immunodeficiency virus-infected men who have sex with men. The NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome, a protein complex composed of NLRP3, apoptosis-associated speck-like protein, and caspase-1, recognizes, and responds to pathogen infection and diverse sterile host-derived or environmental danger signals to induce IL-1β and IL-18 production. Although the Shigella flexneri-mediated activation of the NLRP3 inflammasome has been reported, the effect of S. sonnei on NLRP3 inflammasome activation remains unclear. We found that S. sonnei induced IL-1β production through NLRP3-dependent pathways in lipopolysaccharide-primed macrophages. A mechanistic study revealed that S. sonnei induced IL-1β production through P2X7 receptor-mediated potassium efflux, reactive oxygen species generation, lysosomal acidification, and mitochondrial damage. In addition, the phagocytosis of viable S. sonnei was important for IL-1β production. Furthermore, we demonstrated that NLRP3 negatively regulated phagocytosis and the bactericidal activity of macrophages against S. sonnei. These findings provide mechanistic insight into the activation of the NLRP3 inflammasome by S. sonnei in macrophages.
Highlights
Shigellosis is a bacillary dysentery caused by Gram-negative, nonmotile rod-shaped Shigella species
We found that the level of active caspase1 (p10) in the culture medium of J774A.1 macrophages was increased by S. sonnei infection, as analyzed by Western blotting
The findings of this study clearly showed that S. sonnei infection caused IL1β and IL-18 production through the NLRP3 inflammasome in macrophages, suggesting that S. sonnei infection may increase the risk for NLRP3-associated inflammatory diseases, including diabetes, atherosclerosis, inflammatory bowel disease, chronic kidney disease, gout, and Alzheimer’s disease [13,14,15]
Summary
Shigellosis is a bacillary dysentery caused by Gram-negative, nonmotile rod-shaped Shigella species. There were at least 26 million cases of shigellosis from 1990 to 2016 and 212,438 deaths in 2016 [2]. Each year, ∼500,000 cases of diarrhea and 40 deaths caused by Shigella are reported in the United States [3]. Outbreaks of S. flexneri and S. sonnei among MSM have been reported more frequently in the US, Canada, England, and Spain in recent years [1, 5, 7]. From 2015 to 2016 in Taiwan, an outbreak of shigellosis was reported in MSM living with HIV [8]. Taipei City Hospital isolated S. sonnei from several clinical shigellosis cases in MSM with HIV. Watery or bloody diarrhea caused by S. sonnei is usually relatively mild illness; its spread between MSM by sexual transmission is a public health concern
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