The ALPK1 pathway drives the inflammatory response to Campylobacter jejuni in human intestinal epithelial cells.

Jiannan Cui,Kristel S. van Rooijen,Carlos G. P. Voogdt,Jos P. M. van Putten,Lieneke I. Bouwman,Marcel R. de Zoete,Coco Duizer,Scott D. Gray-Owen

doi:10.1371/journal.ppat.1009787

Jiannan Cui, Kristel S. van Rooijen + Show 6 more

Open Access

https://doi.org/10.1371/journal.ppat.1009787

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Abstract

The Gram-negative bacterium Campylobacter jejuni is a major cause of foodborne disease in humans. After infection, C. jejuni rapidly colonizes the mucus layer of the small and large intestine and induces a potent pro-inflammatory response characterized by the production of a large repertoire of cytokines, chemokines, and innate effector molecules, resulting in (bloody) diarrhea. The virulence mechanisms by which C. jejuni causes this intestinal response are still largely unknown. Here we show that C. jejuni releases a potent pro-inflammatory compound into its environment, which activates an NF-κB-mediated pro-inflammatory response including the induction of CXCL8, CXCL2, TNFAIP2 and PTGS2. This response was dependent on a functional ALPK1 receptor and independent of Toll-like Receptor and Nod-like Receptor signaling. Chemical characterization, inactivation of the heptose-biosynthesis pathway by the deletion of the hldE gene and in vitro engineering identified the released factor as the LOS-intermediate ADP-heptose and/or related heptose phosphates. During C. jejuni infection of intestinal cells, the ALPK1-NF-κB axis was potently activated by released heptose metabolites without the need for a type III or type IV injection machinery. Our results classify ADP-heptose and/or related heptose phosphates as a major virulence factor of C. jejuni that may play an important role during Campylobacter infection in humans.

Highlights

Mucosal surfaces face the continuous challenge of accommodating beneficial microbiota while preventing infection by bacterial pathogens
We identify ADP-heptose and/or related heptose phosphates, released by C. jejuni into its environment during growth, as a novel potent C. jejuni activator of inflammation in intestinal epithelial cells
C. jejuni crosses the mucus layer and colonizes the bottom of the crypts of the colon. This is believed to be followed by breaching of the epithelial layer and triggering of immune responses that lead to a massive neutrophil influx with crypt abscess formation [3,4,5], which likely explains an important part of the acute inflammatory pathology observed during C. jejuni infection

Summary

Introduction

Mucosal surfaces face the continuous challenge of accommodating beneficial microbiota while preventing infection by bacterial pathogens. The difficulty of this task is illustrated by the estimated 3–5 billion cases of gastro-intestinal illness each year [1]. One of the leading causes of human enterocolitis is the bacterial pathogen Campylobacter jejuni. C. jejuni crosses the mucus layer and colonizes the bottom of the crypts of the colon This is believed to be followed by breaching of the epithelial layer and triggering of immune responses that lead to a massive neutrophil influx with crypt abscess formation [3,4,5], which likely explains an important part of the acute inflammatory pathology observed during C. jejuni infection

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