Campylobacter jejuni: targeting host cells, adhesion, invasion, and survival

Abstract

Campylobacter jejuni, causing strong enteritis, is an unusual bacterium with numerous peculiarities. Chemotactically controlled motility in viscous milieu allows targeted navigation to intestinal mucus and colonization. By phase variation, quorum sensing, extensive O-and N-glycosylation and use of the flagellum as type-3-secretion system C. jejuni adapts effectively to environmental conditions. C. jejuni utilizes proteases to open cell-cell junctions and subsequently transmigrates paracellularly. Fibronectin at the basolateral side of polarized epithelial cells serves as binding site for adhesins CadF and FlpA, leading to intracellular signaling, which again triggers membrane ruffling and reduced host cell migration by focal adhesion. Cell contacts of C. jejuni results in its secretion of invasion antigens, which induce membrane ruffling by paxillin-independent pathway. In addition to fibronectin-binding proteins, other adhesins with other target structures and lectins and their corresponding sugar structures are involved in host-pathogen interaction. Invasion into the intestinal epithelial cell depends on host cell structures. Fibronectin, clathrin, and dynein influence cytoskeletal restructuring, endocytosis, and vesicular transport, through different mechanisms. C. jejuni can persist over a 72-h period in the cell. Campylobacter-containing vacuoles, avoid fusion with lysosomes and enter the perinuclear space via dynein, inducing signaling pathways. Secretion of cytolethal distending toxin directs the cell into programmed cell death, including the pyroptotic release of proinflammatory substances from the destroyed cell compartments. The immune system reacts with an inflammatory cascade by participation of numerous immune cells. The development of autoantibodies, directed not only against lipooligosaccharides, but also against endogenous gangliosides, triggers autoimmune diseases. Lesions of the epithelium result in loss of electrolytes, water, and blood, leading to diarrhea, which flushes out mucus containing C. jejuni. Together with the response of the immune system, this limits infection time. Based on the structural interactions between host cell and bacterium, the numerous virulence mechanisms, signaling, and effects that characterize the infection process of C. jejuni, a wide variety of targets for attenuation of the pathogen can be characterized. The review summarizes strategies of C. jejuni for host-pathogen interaction and should stimulate innovative research towards improved definition of targets for future drug development. KEY POINTS: • Bacterial adhesion of Campylobacter to host cells and invasion into host cells are strictly coordinated processes, which can serve as targets to prevent infection. • Reaction and signalling of host cell depend on the cell type. • Campylobacter virulence factors can be used as targets for development of antivirulence drug compounds.

Keywords: Adhesion; Antiadhesion; Campylobacter; Host–pathogen interaction; Invasion; Virulence factors.

Fig. 1

Flagellar apparatus of C. jejuni. Internally, the C-ring generates clockwise or counterclockwise rotation through the motor proteins FliM and FliN, which is transferred to the rod via the MS ring. As the connecting piece of the intracellular space with the extracellular space, the rod transfers this rotation to the hook, and consequently to the filament, which generates the locomotion

Fig. 2

Mechanism of chemotaxis in C. jejuni. As soon as a chemoattractant binds to MCP, a trimeric complex of MCP, CheV and CheAY is formed after signal transduction to the C-terminus. This prevents autophosphorylation of the histidine kinase CheAY. Upon contact with a chemorepellent or in the absence of a chemoattractant, CheV no longer associates with MCP. CheAY autophosphorylates and can subsequently transfer phosphate to the response regulator CheY. The latter associates with FliM in the FliM-FliN complex and thus initiates the tumbling

Fig. 3

Paracellular transmigration of C. jejuni through tight junctions and adherens junctions of intestinal epithelial cells. Secretion of bacterial proteases, such as HtrA, opens cell–cell contacts and the bacterium reaches the basolateral side of the polarized epithelial cells. There, internalization subsequently takes place.

Fig. 4

Internalization of C. jejuni after adhesion to fibronectin. After subvasion, C. jejuni adheres to basolateral Fn of intestinal epithelial cells by interaction with the major adhesins CadF and/or FlpA. Activation of signaling by α5β1-integrins associated to Fn leads to autophosphorylation of the tyrosine kinase FAK. This creates a binding site for the Scr kinase. Scr kinase complex phosphorylates paxillin, which activates Rac1, among others. Finally, Rac1 initiates cellular actin reorganization and membrane ruffling occurs, leading to enclosure of the pathogen