Abstract

The severity of symptoms elicited by the widespread human pathogen Helicobacter pylori is strongly influenced by the genetic diversity of the infecting strain. Among the most important pathogen factors that carry an increased risk for gastric cancer are specific genotypes of the cag pathogenicity island (cag-PAI), encoding a type IV secretion system (T4SS) responsible for the translocation of the CagA effector oncoprotein. To date, little is known about the regulatory events important for the expression of a functional cag-T4SS. Here we demonstrate that the cag-PAI cistrons are subjected to a complex network of direct and indirect transcriptional regulations. We show that promoters of cag operons encoding structural T4SS components display homogeneous transcript levels, while promoters of cag operons encoding accessory factors vary considerably in their basal transcription levels and responses. Most cag promoters are transcriptionally responsive to growth-phase, pH and other stress-factors, although in many cases in a pleiotropic fashion. Interestingly, transcription from the Pcagζ promoter controlling the expression of transglycolase and T4SS stabilizing factors, is triggered by co-culture with a gastric cell line, providing an explanation for the increased formation of the secretion system observed upon bacterial contact with host cells. Finally, we demonstrate that the highly transcribed cagA oncogene is repressed by iron limitation through a direct apo-Fur regulation mechanism. Together the results shed light on regulatory aspects of the cag-PAI, which may be involved in relevant molecular and etiological aspects of H. pylori pathogenesis.

Highlights

  • Helicobacter pylori is a major human pathogen that colonizes the gastric epithelium of more than half of humankind, worldwide

  • The latter is a 38 kb multi-operon locus coding for 28 putative open reading frame (ORF), six of which were identified as homologues of the basic type IV secretion system (T4SS) represented by the Agrobacterium tumefaciens virB operon [3]

  • The H. pylori cag-T4SS promotes injection of the CagA bacterial oncoprotein into host cells [4], as well as a CagA-independent induction of interleukin-8 secretion via the host AP-1 and NF-kB signaling pathways [5]

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Summary

Introduction

Helicobacter pylori is a major human pathogen that colonizes the gastric epithelium of more than half of humankind, worldwide. The severity of symptoms largely depends on the genetic diversity of the infecting strain [2], and on specific genotypes of virulence-associated genes, such as the cag pathogenicity island (cag-PAI). The latter is a 38 kb multi-operon locus coding for 28 putative ORFs, six of which were identified as homologues of the basic type IV secretion system (T4SS) represented by the Agrobacterium tumefaciens virB operon [3]. The H. pylori cag-T4SS promotes injection of the CagA bacterial oncoprotein into host cells [4], as well as a CagA-independent induction of interleukin-8 secretion via the host AP-1 and NF-kB signaling pathways [5]. Host integrin receptors are engaged by the CagL protein to promote

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