Abstract
Campylobacter jejuni is a major cause of bacterial foodborne illness in humans worldwide. Bacterial entry into a host eukaryotic cell involves the initial steps of adherence and invasion, which generally activate several cell-signaling pathways that induce the activation of innate defense systems, which leads to the release of proinflammatory cytokines and induction of apoptosis. Recent studies have reported that the unfolded protein response (UPR), a system to clear unfolded proteins from the endoplasmic reticulum (ER), also participates in the activation of cellular defense mechanisms in response to bacterial infection. However, no study has yet investigated the role of UPR in C. jejuni infection. Hence, the aim of this study was to deduce the role of UPR signaling via induction of ER stress in the process of C. jejuni infection. The results suggest that C. jejuni infection suppresses global protein translation. Also, 12 h of C. jejuni infection induced activation of the eIF2α pathway and expression of the transcription factor CHOP. Interestingly, bacterial invasion was facilitated by knockdown of UPR-associated signaling factors and treatment with the ER stress inducers, thapsigargin and tunicamycin, decreased the invasive ability of C. jejuni. An investigation into the mechanism of UPR-mediated inhibition of C. jejuni invasion showed that UPR signaling did not affect bacterial adhesion to or survival in the host cells. Further, Salmonella Enteritidis or FITC-dextran intake were not regulated by UPR signaling. These results indicated that the effect of UPR on intracellular intake was specifically found in C. jejuni infection. These findings are the first to describe the role of UPR in C. jejuni infection and revealed the participation of a new signaling pathway in C. jejuni invasion. UPR signaling is involved in defense against the early step of C. jejuni invasion and thus presents a potential therapeutic target for the treatment of C. jejuni infection.
Highlights
Campylobacter jejuni is a Gram-negative microaerophilic bacterium that is a major cause of foodborne gastrointestinal illness in humans worldwide [1]
The translational products were detected with puromycin-specific antibody, which showed that the global protein translation in C. jejuni-infected cells had decreased (Fig 1A and 1B)
During C. jejuni infection, mRNA expression levels of endoplasmic reticulum (ER)-associated transcription factors, such as C/EBP-homologous protein (CHOP) and growth arrest and DNA damage-inducible protein-34 (GADD34), were up-regulated after infection for 12 h (Fig 1C and 1D). These data suggest that unfolded proteins had accumulated, and ER stress was induced by C. jejuni infection
Summary
Campylobacter jejuni is a Gram-negative microaerophilic bacterium that is a major cause of foodborne gastrointestinal illness in humans worldwide [1]. C. jejuni infection induces several intestinal inflammation-associated clinical symptoms, such as diarrhea, abdominal pain, and fever. Despite the severity of gastrointestinal symptoms, genomic studies have been unsuccessful in the identification of the specific virulence factors of C. jejuni. Previous in vitro studies revealed that multifactorial virulence factors participate in bacterial secretion, motility, adherence, and invasion in the pathogenesis of C. jejuni. The adhesion and invasion processes are closely associated with the ability of C. jejuni to induce inflammation, as defective adherence and invasion of C. jejuni strains were found to decrease the production of proinflammatory cytokines, such as interleukin (IL)-8, in cultured intestinal epithelial cells [2]. The adherence and invasion processes are key to the pathogenesis of C. jejuni
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