Glucose 6P Binds and Activates HlyIIR to Repress Bacillus cereus Haemolysin hlyII Gene Expression

Elisabeth Guillemet,Didier Rognan,Seav-Ly Tran,Nalini Ramarao,Céline Cadot,Didier Lereclus,Willem Van Schaik

doi:10.1371/journal.pone.0055085

Abstract

Bacillus cereus is a Gram-positive spore-forming bacterium causing food poisoning and serious opportunistic infections. These infections are characterized by bacterial accumulation despite the recruitment of phagocytic cells. We have previously shown that B. cereus Haemolysin II (HlyII) induces macrophage cell death by apoptosis. In this work, we investigated the regulation of the hlyII gene. We show that HlyIIR, the negative regulator of hlyII expression in B. cereus, is especially active during the early bacterial growth phase. We demonstrate that glucose 6P directly binds to HlyIIR and enhances its activity at a post-transcriptional level. Glucose 6P activates HlyIIR, increasing its capacity to bind to its DNA-box located upstream of the hlyII gene, inhibiting its expression. Thus, hlyII expression is modulated by the availability of glucose. As HlyII induces haemocyte and macrophage death, two cell types that play a role in the sequestration of nutrients upon infection, HlyII may induce host cell death to allow the bacteria to gain access to carbon sources that are essential components for bacterial growth.

Highlights

The Bacillus cereus group is composed of highly related pathogenic species, including B. thuringiensis, an insect pathogen, B. anthracis, the etiological agent of anthrax and B. cereus
Several studies using heterologous hosts have shown that HlyIIR is a negative regulator of hlyII gene transcription
HlyIIR is a negative regulator of hlyII expression in B. cereus and is especially active during the early phase of bacterial growth

Summary

Introduction

The Bacillus cereus group is composed of highly related pathogenic species, including B. thuringiensis, an insect pathogen, B. anthracis, the etiological agent of anthrax and B. cereus. B. cereus is associated with severe local and systemic human infections, posing a public health problem [3]. Infections such as endophthalmitis, pneumonia and meningitis, in neonates in which they may cause death of the infant within days, have been attributed to B. cereus [4,5,6,7]. B. cereus spores survive, germinate and multiply in contact with macrophages [14], eventually leading to the production of toxins [15] Among these toxins, the haemolysin HlyII has been shown to be responsible for macrophage death [15,16]. The importance of HlyII has been strengthened by the fact that the hlyII gene is present in several clinical isolates of B. cereus [25]

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