MtrR Control of a Transcriptional Regulatory Pathway in Neisseria meningitidis That Influences Expression of a Gene (nadA) Encoding a Vaccine Candidate

Abstract

The surface-exposed NadA adhesin produced by a subset of capsular serogroup B strains of Neisseria meningitidis is currently being considered as a vaccine candidate to prevent invasive disease caused by a hypervirulent lineage of meningococci. Levels of NadA are known to be controlled by both transcriptional regulatory factors and a component of human saliva, 4-hydroxyphenylacetic acid. Herein, we confirmed the capacity of a DNA-binding protein termed FarR to negatively control nadA expression. We also found that a known transcriptional regulator of farR in N. gonorrhoeae termed MtrR can have a negative regulatory impact on farR and nadA expression, especially when over-expressed. MtrR-mediated repression of nadA was found to be direct, and its binding to a target DNA sequence containing the nadA promoter influenced formation and/or stability of FarR::nadA complexes. The complexity of the multi-layered regulation of nadA uncovered during this investigation suggests that N. meningitidis modulates NadA adhesin protein levels for the purpose of interacting with host cells yet avoiding antibody directed against surface exposed epitopes.

4-Hydroxyphenylacetic Acid Attenuated Inflammation and Edema via Suppressing HIF-1α in Seawater Aspiration-Induced Lung Injury in Rats

“…It is also an active component of some Chinese herb such as Aster tataricus and Rhodiola rosea , as well as an intermediate product of chemical synthesis of atenolol (β-receptor blocking agent) and puerarin (active component of Lobed Kudzuvine Root ). Some previous studies reported that 4-HPA controlled the NadA gene expression and could become a potential hypopigmenting agent [23,24,25]. Our results suggested that 4-HPA was a good inhibitor of hypertonicity, hypoxia, or both of the two-induced HIF-1α expression.…”

“…Some previous studies reported that 4-HPA, a metabolite of aromatic amino acid catabolism that is secreted in saliva, controlled the NadA gene expression and could become a potential hypopigmenting agent [23,24,25]. We also found that Aster tataricus extract and 4-HPA could inhibit HIF-1α expression in our preliminary experiments.…”

An international invasive meningococcal disease outbreak due to a novel and rapidly expanding serogroup W strain, Scotland and Sweden, July to August 2015

“…MtrR has also recently been implicated in the regulation of nadA expression in the meningococcus. NadA is a major surface antigen and a virulence factor involved in adherence and invasion [26,27]. It is also a component of the multicomponent vaccine developed to target serogroup B meningococci (Bexsero) and the likely target of corresponding protection that has been demonstrated against isolates of the original UK W:cc11 strain [28].…”

Molecular Basis of Ligand-Dependent Regulation of NadR, the Transcriptional Repressor of Meningococcal Virulence Factor NadA

“…Previous studies revealed that nadA expression levels are mainly regulated by the Neisseria adhesin A Regulator (NadR) [ 7 ]. Although additional factors influence nadA expression, we focused on its regulation by NadR, the major mediator of NadA phase variable expression [ 8 , 9 ]. Studies of NadR also have broader implications, since a genome-wide analysis of MenB wild-type and nadR knock-out strains revealed that NadR influences the regulation of > 30 genes, including maf genes, from the m ultiple a dhesin f amily [ 10 ].…”