Host epithelial cell invasion by Campylobacter jejuni: trigger or zipper mechanism?

Abstract

Campylobacter jejuni, a spiral-shaped Gram-negative pathogen, is a highly frequent cause of gastrointestinal foodborne illness in humans worldwide. Clinical outcome of C. jejuni infections ranges from mild to severe diarrheal disease, and some other complications including reactive arthritis and Guillain-Barré syndrome. This review article highlights various C. jejuni pathogenicity factors, host cell determinants, and proposed signaling mechanisms involved in human host cell invasion and their potential role in the development of C. jejuni-mediated disease. A model is presented which outlines the various important interactions of C. jejuni with the intestinal epithelium, and we discuss the pro's and con's for the "zipper" over the "trigger" mechanism of invasion. Future work should clarify the contradictory role of some previously identified factors, and should identify and characterize novel virulence determinants, which are crucial to provide fresh insights into the diversity of strategies employed by this pathogen to cause disease.

Keywords: cellular invasion; molecular pathogenesis; signaling; virulence.

Figure 1

Primary mechanisms of bacterial invasion into non-phagocytic host cells. Schematic representation of the two different routes of entry by intracellular bacterial pathogens. The pathogens induce their own uptake into target cells by subversion of host cell signaling pathways using the “zipper” and “trigger” invasion mechanism, respectively. (A) Bacterial gastrointestinal pathogens commonly colonize the gastric epithelium [step 1]. The “zipper” mechanism of invasion involves the high-affinity binding of bacterial surface adhesins to their cognate receptors on mammalian cells [step 2], which is required to initiate cytoskeleton-mediated zippering of the host cell plasma membrane around the bacterium [step 3]. Subsequently the bacterium is internalized into a vacuole. Some bacteria have developed strategies to survive within, or to escape from this compartment [step 4]. (B) The “trigger” mechanism is used by Shigella or Salmonella spp. which also colonize the intestinal epithelium [step 1]. These pathogens use sophisticated type-III or type-IV secretion system to inject various effector proteins into the host cell cytoplasm [step 2]. These factors manipulate a variety of signaling events including the activation of small Rho GTPases and cytoskeletal reorganization to induce membrane ruffling and subsequently bacterial uptake [step 3]. As a consequence of this signaling, the bacteria are internalized into a vacuole [step 4], followed by the induction of different signaling pathways for intracellular survival and trafficking. This figure was adapted from Tegtmeyer et al. (2011) with kind permission from Springer Publishing. (C) Scanning electron microscopy of C. jejuni 81-176 invasion. Invading bacteria (yellow arrows) were regularly associated with membrane ruffles (red arrows) and filopodia-like structures (blue arrows). This figure was adapted from Boehm et al. (2012). (D) Electron micrographs of C. jejuni–containing vacuoles (CCVs) that do not co-localize with BSA-gold (left) and CCVs that co-localize with BSA-Gold and resemble lysosomes (right, arrows) are shown. The two pictures were kindly provided by Dr. Galan (Watson and Galán, 2008). (E) The electron micrograph of translocating C. jejuni across polarized Caco-2 cells by the paracellular pathway was kindly provided by Dr. Konkel (Konkel et al., 1992b).

Figure 2

Hypothetical model for C. jejuni-induced signaling events leading to bacterial invasion and establishing infections. C. jejuni adheres to host cells via numerous reported and unknown factors. Several indicated host cell receptors have been proposed to play a role in the uptake of the bacteria. This potentially causes localized F-actin and/or microtubule rearrangements at the site of C. jejuni entry, resulting in engulfment and bacterial uptake. Several indicated host cell signaling molecules and pathways including the intracellular survival in Campylobacter-containing vacuoles (CCVs) have been reported in in vitro infection models and may play a role during pathogenesis in vivo. For more details, see tables and text.