Novel Clinical Campylobacter jejuni Infection Models Based on Sensitization of Mice to Lipooligosaccharide, a Major Bacterial Factor Triggering Innate Immune Responses in Human Campylobacteriosis

Abstract

: Human Campylobacter jejuni infections inducing campylobacteriosis including post-infectious sequelae such as Guillain-Barré syndrome and reactive arthritis are rising worldwide and progress into a global burden of high socioeconomic impact. Intestinal immunopathology underlying campylobacteriosis is a classical response of the innate immune system characterized by the accumulation of neutrophils and macrophages which cause tissue destruction, barrier defects and malabsorption leading to bloody diarrhea. Clinical studies revealed that enteritis and post-infectious morbidities of human C. jejuni infections are strongly dependent on the structure of pathogenic lipooligosaccharides (LOS) triggering the innate immune system via Toll-like-receptor (TLR)-4 signaling. Compared to humans, mice display an approximately 10,000 times weaker TLR-4 response and a pronounced colonization resistance (CR) against C. jejuni maintained by the murine gut microbiota. In consequence, investigations of campylobacteriosis have been hampered by the lack of experimental animal models. We here summarize recent progress made in the development of murine C. jejuni infection models that are based on the abolishment of CR by modulating the murine gut microbiota and by sensitization of mice to LOS. These advances support the major role of LOS driven innate immunity in pathogenesis of campylobacteriosis including post-infectious autoimmune diseases and promote the preclinical evaluation of novel pharmaceutical strategies for prophylaxis and treatment.

Keywords: Campylobacter jejuni; campylobacteriosis; intestinal pathogenesis; lipooligosaccharide (LOS); pathogenicity; toll-like receptor.

Figure 1

Campylobacter jejuni induced immunopathological responses within the intestinal tract. The highly motile C. jejuni circumvent the mucus layer, cross the intestinal epithelial layer and interact with mucosal and lamina propria cells, resulting in the recruitment of dendritic cells, macrophages, and neutrophils. The interaction of these innate immune cells with the lipooligosaccharide (LOS) of C. jejuni mounts a massive pro-inflammatory cytokine response via TLR-4 signaling, inducing apoptosis and ulcerations in the epithelial layer, progressing into barrier defects, malabsorption and bloody diarrhea.

Figure 2

The basal structure of C. jejuni LOS. The LOS of C. jejuni consists of Lipid A, phostoethanolamine (PEA), 3-Deoxy-d-manno-oct-2-ulosonic acid or keto-deoxyoctulosonate (Kdo), Heptose (Hep), glucose (Glu), galactose (Gal), N-acetylgalactosamine (GalNAc), and N-acetylneuraminic acid (Neu5Ac) and in sialylated form mimics a range of gangliosides (e.g., GM1). The characteristic O-antigen of LPS from Gram-negative bacteria is missing.

Figure 3

C. jejuni LOS and TLR-4 Signaling. The activation of TLR-4 leads to the synthesis of inflammatory mediators via two different pathways; TRIF-TRAM pathway, which induces the secretion of tumor necrosis factor alpha and TIRAP-MyD88, which is responsible for the LOS response and NF-κB activation.

Figure 4

Modulation of Campylobacter jejuni infection by host and dietary factors. Both host and dietary factors interact with the immune responses upon C. jejuni infection at different levels thereby affecting the outcome of disease.