Abstract
Salmonella is one of the most important worldwide zoonotic pathogens. After invading a host orally, the bacteria break through the intestinal epithelial barrier for further invasion. Intestinal epithelial cells (IECs) play a crucial role in maintaining the integrity of the intestinal epithelial barrier. Necroptosis is considered one of the virulence strategies utilized by invasive Salmonella. Our previous work has shown that SpvB, an effector encoded by S. Typhimurium virulence plasmid (pSLT), promotes bacterial translocation via the paracellular route. However, it is still unknown whether SpvB could promote bacterial invasion through disrupting the integrity of IECs. Here, we demonstrated that SpvB promoted necroptosis of IECs and contributed to the destruction of the intestinal barrier during Salmonella infection. We found that SpvB enhanced the protein level of receptor-interacting protein kinase 3 (RIPK3) through inhibiting K48-linked poly-ubiquitylation of RIPK3 and the degradation of the protein in an autophagy-dependent manner. The abundant accumulation of RIPK3 upregulated the phosphorylation of MLKL, which contributed to necroptosis. The damage to IECs ultimately led to the disruption of the intestinal barrier and aggravated infection. In vivo, SpvB promoted the pathogenesis of Salmonella, favoring intestinal injury and colonic necroptosis. Our findings reveal a novel function of Salmonella effector SpvB, which could facilitate salmonellosis by promoting necroptosis, and broaden our understanding of the molecular mechanisms of bacterial invasion.
Highlights
Salmonella is a common foodborne pathogen that poses an urgent health-safety problem
We reported a novel function of the effector SpvB to confirm these findings; the results showed that GSK’872 elimidisrupt the integrity of the intestinal epithelial barrier by inducing nated the significant difference in cell death among the three the necroptosis of Intestinal epithelial cells (IECs), promoting the invasion of Salmonella. infected groups (Fig. 2D)
By detecting the release of lactate dehydrogenase (LDH), an established indicator of cell death, we found that ΔpSLT, Result 3 SpvB promotes IECs necroptosis in a manner
Summary
Salmonella is a common foodborne pathogen that poses an urgent health-safety problem. While most serovars cause mild gastroenteritis, some serovars in individuals with weakened immune systems can lead to severe and invasive infections, such as enteric fever and invasive nontyphoidal Salmonella disease, resulting in long-term health consequences and even death [2, 3]. Typhimurium infection generally causes obvious intestinal injury and cell death. Necroptosis has been implicated in many pathologies, such as inflammatory bowel disease It is triggered by the dysregulation of either extracellular or intracellular homeostasis and requires the activity of mixed-lineage kinase domainlike protein (MLKL) and receptor-interacting protein kinase 3 (RIPK3). We reported a novel function of the effector SpvB to confirm these findings; the results showed that GSK’872 elimidisrupt the integrity of the intestinal epithelial barrier by inducing nated the significant difference in cell death among the three the necroptosis of IECs, promoting the invasion of Salmonella. Human cervical carcinoma cells (HeLa), deficient in RIPK3 expression [15], were used to investigate the
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