Abstract
Salmonella pathogenesis studies to date have focused on Salmonella typhimurium, and the pathogenesis of a second major serotype, Salmonella enteritidis, is poorly understood. Salmonella spp. possess effector proteins that display biochemical activities and modulate host functions. Here, we generated a deletion mutant of the effector AvrA, S.E-AvrA-, and a plasmid-mediated complementary strain, S.E-AvrA-/pAvrA+ (S.E-AvrA+), in S. Enteritidis. Using in vitro and in vivo infection models, we showed that AvrA stabilizes epithelial tight junction (TJ) proteins, such as ZO-1, in human intestinal epithelial cells. Transepithelial electrical resistance was significantly higher in cells infected with S.E-AvrA+ than in cells infected with S.E-AvrA- Inhibition of the JNK pathway suppresses the disassembly of TJ proteins; we found that enteritidis AvrA inhibited JNK activity in cells infected with wild type or S.E-AvrA+ strains. Therefore, Enteritidis AvrA-induced ZO-1 stability is achieved via suppression of the JNK pathway. Furthermore, the S.E-AvrA- strain led to enhanced bacterial invasion, both in vitro and in vivo Taken together, our data reveal a novel role for AvrA in S. Enteritidis: Enteritidis AvrA stabilizes intestinal TJs and attenuates bacterial invasion. The manipulation of JNK activity and TJs in microbial-epithelial interactions may be a novel therapeutic approach for the treatment of infectious diseases.
Highlights
Salmonella pathogenesis studies to date have focused on Salmonella typhimurium, and the pathogenesis of a second major serotype, Salmonella enteritidis, is poorly understood
Using in vitro and in vivo infection models, we showed that AvrA stabilizes epithelial tight junction (TJ) proteins, such as ZO-1, in human intestinal epithelial cells
Inhibition of the JNK pathway suppresses the disassembly of TJ proteins; we found that enteritidis AvrA inhibited JNK activity in cells infected with wild type or S.E-AvrA؉ strains
Summary
S. Enteritidis AvrA Stabilizes Intestinal Tight Junctions occludens (ZO), such as ZO-1, ZO-2, and ZO-3 [27, 28], which separate the apical and basolateral cell surfaces to provide a barrier function, inhibit solute and water flow through the paracellular space, and inhibit bacterial invasion [29]. The JNKs were originally identified based on their activation in response to environmental stress stimuli, such as bacterial infection. The JNK pathway plays a role in regulating TJ integrity in different epithelial cells [25, 35, 36]. Enteritidis AvrA stabilizes intestinal epithelial TJs and decreases bacterial invasion. Enteritidis-infected intestinal epithelial cells and a mouse colitis model, we found that enteritidis AvrA may reprogram the regulation of TJs in eukaryotic cells to benefit the pathogen
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