HexR controls glucose-responsive genes and central carbon metabolism in Neisseria meningitidis

Neisseria meningitidis, an exclusively human pathogen and the leading cause of bacterial meningitis, must adapt to different host niches during human infection. N. meningitidis can utilize a restricted range of carbon sources, including lactate, glucose and pyruvate, whose concentration varies in host niches. Microarray analysis of N. meningitidis grown in chemically defined medium in the presence or absence of glucose allowed us to identify genes regulated by carbon source availability. Most of these genes are implicated in energy metabolism and transport as well as some implicated in virulence. In particular, genes involved in glucose catabolism were up-regulated whereas genes involved in the TCA cycle were down-regulated. Several genes encoding surface exposed proteins were up-regulated in the presence of glucose, including the MafA adhesins and the Neisseria surface protein A. Our microarray analysis led to the identification of a glucose-responsive hexR-like transcriptional regulator that controls genes of the central carbon metabolism of N. meningitidis in response to glucose. We characterized the HexR regulon and showed the hexR gene is accountable for a subset of the glucose-responsive regulation, and in vitro assays with the purified protein showed that HexR binds to the promoters of the central metabolic operons of the bacterium. Based on DNA sequence alignment of the target sites we propose a 17-bp pseudo-palindromic HexR consensus binding motif. Furthermore, N. meningitidis strains lacking hexR expression are deficient in establishing successful bacteremia in an infant rat model of infection, indicating the importance of this regulator for the survival of this pathogen in vivo.