Function of Serine Protease HtrA in the Lifecycle of the Foodborne Pathogen Campylobacter jejuni

Abstract

Campylobacter jejuni is a major food-borne zoonotic pathogen, responsible for a large proportion of bacterial gastroenteritis cases, as well as Guillian-Barré and Miller-Fisher syndromes. During infection, tissue damage is mainly caused by bacteria invading epithelial cells and traversing the intestinal barrier. C. jejuni is able to enter the lamina propria and the bloodstream and may move into other organs, such as spleen, liver, or mesenteric lymph nodes. However, the involved molecular mechanisms are not fully understood. C. jejuni can transmigrate effectively across polarized intestinal epithelial cells mainly by the paracellular route using the serine protease high-temperature requirement A (HtrA). However, it appears that HtrA has a dual function, as it also acts as a chaperone, interacting with denatured or misfolded periplasmic proteins under stress conditions. Here, we review recent progress on the role of HtrA in C. jejuni pathogenesis. HtrA can be transported into the extracellular space and cleaves cell-to-cell junction factors, such as E-cadherin and probably others, disrupting the epithelial barrier and enabling paracellular transmigration of the bacteria. The secretion of HtrA is a newly discovered strategy also utilized by other pathogens. Thus, secreted HtrA proteases represent highly attractive targets for anti-bacterial treatment and may provide a suitable candidate for vaccine development.

Keywords: C. jejuni proteases; E-cadherin; HtrA; LOS; TER; adherens junction; cellular invasion; fibronectin; integrins; molecular pathogenesis; occludin; outer membrane vesicles (OMVs); signaling; tight junction; virulence.

Figure 1.

Domain architecture of HtrA, secretion routes of the protease, and involvement in virulence properties by C. jejuni. (A) Representation of the domain structure of characteristic HtrA family proteases. The protease domain is shown in yellow, PDZ-1 and PDZ-2 domains in red, and the three conserved amino acid residues (histidine, aspartate, and serine; HDS) at the active centre in green. A signal peptide is highlighted in light blue squares and a transmembrane (TM) domain with magenta. (B) Proposed secretion routes of C. jejuni HtrA into the extracellular space are diverse and complex. As shown in this scheme, HtrA can be presented at the bacterial cell surface (1), delivered in the supernatant as soluble protein (2), or shed in the form of outer membrane vesicles (OMVs) (3). (C) HtrA proteases are involved in C. jejuni stress management (1), as well as cleavage of host cell factors such as E-cadherin in the adherens junctions (AJs) and possibly other factors, such as occludin in the tight junctions (TJs) (2), followed by opening of cell-to-cell junctions (3). Cleavage of junctional proteins leads to disruption of the epithelial barrier (4), paving the way for bacteria to transmigrate across the cell monolayer by a paracellular route (5) and to enter deeper tissues (6). In addition, HtrA is also involved in bacterial adhesion by a yet unknown mechanism (7), basolateral targeting of fibronectin by CadF (8), and CadF-dependent invasion of host target cells (9)