Abstract
Salmonella Typhimurium is a major cause of human gastroenteritis. The Salmonella type III secretory system secretes virulence proteins, called effectors. Effectors are responsible for the alteration of tight junction (TJ) structure and function in intestinal epithelial cells. AvrA is a newly described bacterial effector found in Salmonella. We report here that AvrA expression stabilizes cell permeability and tight junctions in intestinal epithelial cells. Cells colonized with an AvrA-deficient bacterial strain (AvrA−) displayed decreased cell permeability, disruption of TJs, and an increased inflammatory response. Western blot data showed that TJ proteins, such as ZO-1, claudin-1, decreased after AvrA- colonization for only 1 hour. In contrast, cells colonized with AvrA-sufficient bacteria maintained cell permeability with stabilized TJ structure. This difference was confirmed in vivo. Fluorescent tracer studies showed increased fluorescence in the blood of mice infected with AvrA- compared to those infected with the AvrA-sufficient strains. AvrA- disrupted TJ structure and function and increased inflammation in vivo, compared to the AvrA- sufficient strain. Additionally, AvrA overexpression increased TJ protein expression when transfected into colonic epithelial cells. An intriguing aspect of this study is that AvrA stabilized TJs, even though the other TTSS proteins, SopB, SopE, and SopE2, are known to disrupt TJs. AvrA may play a role in stabilizing TJs and balancing the opposing action of other bacterial effectors. Our findings indicate an important role for the bacterial effector AvrA in regulation of intestinal epithelial cell TJs during inflammation. The role of AvrA represents a highly refined bacterial strategy that helps the bacteria survive in the host and dampen the inflammatory response.
Highlights
Intestinal epithelial cells participate in immune regulation and mucosal integrity
While examining changes in resistance and cell permeability, we investigated tight junction (TJ) protein expression, as well as effects on TJ protein distribution induced by AvrA absence in the bacterial strain (AvrA-)deficient and -sufficient bacterial strains in vitro and in vivo
AvrA expression alters tight junction protein expression in human epithelial cells First, we analyzed whether infection of T84 cell monolayers with AvrA protein-sufficient or -deficient bacterial strains could influence the expression of the major proteins which comprise the tight junction complex
Summary
Intestinal epithelial cells participate in immune regulation and mucosal integrity. Tight junctions (TJs) constitute continuous circumferential seals around cells and serve as a protective barrier, preventing solutes and water from passing freely through the paracellular pathway. Tight junctions can be altered by various pathogens, as well as by their toxins. These effects may result from direct modification of TJ proteins such as occludin, claudin, and ZO-1, or by alteration of the perijunctional actomyosin ring [1,2,3]. TJ disruption is dependent on the type III secretory system (TTSS) of Salmonella. TTSS is a needle-like protein transport device used by Gram-negative pathogenic bacteria. TTSS is encoded by the Salmonella pathogenicity island 1 (SPI-1) [9].
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