In the NadR Regulon, Adhesins and Diverse Meningococcal Functions Are Regulated in Response to Signals in Human Saliva

Fagnocchi, Luca; Pigozzi, Eva; Scarlato, Vincenzo; Delany, Isabel

doi:10.1128/jb.06161-11

Cited by 28 publications

(43 citation statements)

References 43 publications

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“…The N. meningitidis strains used in this study are listed in Table 1 and include the respective NadR null mutant derivatives, which have been described elsewhere (23). The NGP165 NHBA null mutant was generated as described previously (12).…”

Section: Methodsmentioning

confidence: 99%

“…4-HPA is a catabolite of aromatic amino acids and is commonly found in human saliva (22). It has also been recently reported that human saliva itself can induce NadA expression as well as 4-HPA, suggesting that signals capable of inducing NadA expression, which can be mimicked by 4-HPA in vitro, are present in the oropharyngeal niche of meningococcal colonization (23). Moreover, it has also been demonstrated that sera from children convalescent after meningococcal disease are able to recognize NadA, suggesting that NadA is expressed during invasive human infection to a level which is sufficient to elicit anti-NadA antibodies (24).…”

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confidence: 99%

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Transcriptional Regulation of the nadA Gene in Neisseria meningitidis Impacts the Prediction of Coverage of a Multicomponent Meningococcal Serogroup B Vaccine

et al. 2013

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bThe NadA adhesin is a major component of 4CMenB, a novel vaccine to prevent meningococcus serogroup B (MenB) infection. Under in vitro growth conditions, nadA is repressed by the regulator NadR and poorly expressed, resulting in inefficient killing of MenB strains by anti-NadA antibodies. Interestingly, sera from children infected with strains that express low levels of NadA in laboratory growth nevertheless recognize the NadA antigen, suggesting that NadA expression during infection may be different from that observed in vitro. In a strain panel covering a range of NadA levels, repression was relieved through deleting nadR. All nadR knockout strains expressed high levels of NadA and were efficiently killed by sera from subjects immunized with 4CMenB. A selected MenB strain, NGP165, mismatched for other vaccine antigens, is not killed by sera from immunized infants when the strain is grown in vitro. However, in an in vivo passive protection model, the same sera effectively protected infant rats from bacteremia with NGP165. Furthermore, we identify a novel hydroxyphenylacetic acid (HPA) derivative, reported by others to be produced during inflammation, which induces expression of NadA in vitro, leading to efficient antibody-mediated killing. Finally, using bioluminescent reporters, nadA expression in the infant rat model was induced in vivo at 3 h postinfection. Our results suggest that during infectious disease, NadR repression is alleviated due to niche-specific signals, resulting in high levels of NadA expression from any nadA-positive (nadA ؉ ) strain and therefore efficient killing by anti-NadA antibodies elicited by the 4CMenB vaccine.

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Section: Methodsmentioning

confidence: 99%

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confidence: 99%

Transcriptional Regulation of the nadA Gene in Neisseria meningitidis Impacts the Prediction of Coverage of a Multicomponent Meningococcal Serogroup B Vaccine

et al. 2013

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“…Further, children recovering from invasive meningococcal disease produce specific antibody responses against this antigen (11). NadA expression is regulated at the transcriptional level by the length variation of a tandem repeat region located in the gene promoter (12,13), with expression regulated by NadR, a repressor molecule (14)(15)(16). Expression can be induced by the use of 4-hydroxyphenyl acetic acid, a small molecule secreted in human saliva, which inhibits NadRdependent repression (14).…”

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confidence: 99%

Neisseria Adhesin A Variation and Revised Nomenclature Scheme

Bambini¹,

Chiara²,

Muzzi³

et al. 2014

Clin. Vaccine Immunol.

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c Neisseria adhesin A (NadA), involved in the adhesion and invasion of Neisseria meningitidis into host tissues, is one of the major components of Bexsero, a novel multicomponent vaccine licensed for protection against meningococcal serogroup B in Europe, Australia, and Canada. NadA has been identified in approximately 30% of clinical isolates and in a much lower proportion of carrier isolates. Three protein variants were originally identified in invasive meningococci and named NadA-1, NadA-2, and NadA-3, whereas most carrier isolates either lacked the gene or harbored a different variant, NadA-4. Further analysis of isolates belonging to the sequence type 213 (ST-213) clonal complex identified NadA-5, which was structurally similar to NadA-4, but more distantly related to NadA-1, -2, and -3. At the time of this writing, more than 89 distinct nadA allele sequences and 43 distinct peptides have been described. Here, we present a revised nomenclature system, taking into account the complete data set, which is compatible with previous classification schemes and is expandable. The main features of this new scheme include (i) the grouping of the previously named NadA-2 and NadA-3 variants into a single NadA-2/3 variant, (ii) the grouping of the previously assigned NadA-4 and NadA-5 variants into a single NadA-4/5 variant, (iii) the introduction of an additional variant (NadA-6), and (iv) the classification of the variants into two main groups, named groups I and II. To facilitate querying of the sequences and submission of new allele sequences, the nucleotide and amino acid sequences are available at http://pubmlst.org/neisseria/NadA/.

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“…6). This can have physiologically relevant consequences, since gapA was shown to play a role in adhesion (51) and its expression is controlled by the NadR repressor (20). Furthermore, the acetate kinase gene ackA2, which is involved in the production of acetate from acetyl coenzyme A (acetyl-CoA), was downregulated by glucose (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Accordingly, about one-half of the genes that are essential for systemic infection encode enzymes that are involved in the metabolism and transport of nutrients (15). In addition, several environmental signals have effects on the transcriptional regulation of N. meningitidis during host infections, as shown for iron (16,17), zinc (18), nitric oxide (19), human saliva (20), and human blood (21,22). Therefore, virulence factors and genes essential for survival need to be regulated tightly and rapidly at the gene expression level in order to respond to the various microenvironments encountered during infection.…”

Section: Importancementioning

confidence: 99%

HexR Controls Glucose-Responsive Genes and Central Carbon Metabolism in Neisseria meningitidis

Antunes¹,

Golfieri²,

Ferlicca³

et al. 2016

J Bacteriol

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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 concentrations vary in host niches. Microarray analysis of N. meningitidis grown in a chemically defined medium in the presence or absence of glucose allowed us to identify genes regulated by carbon source availability. Most such genes are implicated in energy metabolism and transport, and some are implicated in virulence. In particular, genes involved in glucose catabolism were upregulated, whereas genes involved in the tricarboxylic acid cycle were downregulated. Several genes encoding surface-exposed proteins, including the MafA adhesins and Neisseria surface protein A, were upregulated in the presence of glucose. 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 that the hexR gene is accountable for some of the glucose-responsive regulation; 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 pseudopalindromic consensus HexR binding motif. Furthermore, N. meningitidis strains lacking hexR expression were 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. IMPORTANCENeisseria meningitidis grows on a limited range of nutrients during infection. We analyzed the gene expression of N. meningitidis in response to glucose, the main energy source available in human blood, and we found that glucose regulates many genes implicated in energy metabolism and nutrient transport, as well as some implicated in virulence. We identified and characterized a transcriptional regulator (HexR) that controls metabolic genes of N. meningitidis in response to glucose. We generated a mutant lacking HexR and found that the mutant was impaired in causing systemic infection in animal models. Since N. meningitidis lacks known bacterial regulators of energy metabolism, our findings suggest that HexR plays a major role in its biology by regulating metabolism in response to environmental signals.

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In the NadR Regulon, Adhesins and Diverse Meningococcal Functions Are Regulated in Response to Signals in Human Saliva

Cited by 28 publications

References 43 publications

Transcriptional Regulation of the nadA Gene in Neisseria meningitidis Impacts the Prediction of Coverage of a Multicomponent Meningococcal Serogroup B Vaccine

Transcriptional Regulation of the nadA Gene in Neisseria meningitidis Impacts the Prediction of Coverage of a Multicomponent Meningococcal Serogroup B Vaccine

Neisseria Adhesin A Variation and Revised Nomenclature Scheme

HexR Controls Glucose-Responsive Genes and Central Carbon Metabolism in Neisseria meningitidis

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