title: Influence of the combination and phase variation status of the haemoglobin receptors HmbR and HpuAB on meningococcal virulence.
abstract: Neisseria meningitidis can utilize haem, haemoglobin and haemoglobin-haptoglobin complexes as sources of iron via two TonB-dependent phase variable haemoglobin receptors, HmbR and HpuAB. HmbR is over-represented in disease isolates, suggesting a link between haemoglobin acquisition and meningococcal disease. This study compared the distribution of HpuAB and phase variation (PV) status of both receptors in disease and carriage isolates. Meningococcal disease (n = 214) and carriage (n = 305) isolates representative of multiple clonal complexes (CCs) were investigated for the distribution, polyG tract lengths and ON/OFF status of both haemoglobin receptors, and for the deletion mechanism for HpuAB. Strains with both receptors or only hmbR were present at similar frequencies among meningococcal disease isolates as compared with carriage isolates. However, >90 % of isolates from the three CCs CC5, CC8 and CC11 with the highest disease to carriage ratios contained both receptors. Strains with an hpuAB-only phenotype were under-represented among disease isolates, suggesting selection against this receptor during systemic disease, possibly due to the receptor having a high level of immunogenicity or being inefficient in acquisition of iron during systemic spread. Absence of hpuAB resulted from either complete deletion or replacement by an insertion element. In an examination of PV status, one or both receptors were found in an ON state in 91 % of disease and 71 % of carriage isolates. We suggest that expression of a haemoglobin receptor, either HmbR or HpuAB, is of major importance for systemic spread of meningococci, and that the presence of both receptors contributes to virulence in some strains.
authors.affiliation: Department of Genetics, University of Leicester, Leicester LE1 7RH, UK.
authors.forename: Isfahan
authors.initials: I
authors.lastname: Tauseef
authors.affiliation: The Department of Zoology, University of Oxford, South Parks Road, Oxford OX1 3SY, UK.
authors.forename: Odile B
authors.initials: OB
authors.lastname: Harrison
authors.affiliation: Molecular Bacteriology and Immunology Group, University of Nottingham, Nottingham, UK.
authors.forename: Karl G
authors.initials: KG
authors.lastname: Wooldridge
authors.affiliation: National Institute for Biological Standards and Control, Blanche Lane, South Mimms, Hertfordshire EN6 3QG, UK.
authors.forename: Ian M
authors.initials: IM
authors.lastname: Feavers
authors.affiliation: School of Community Health Sciences, University of Nottingham, Nottingham, UK.
authors.forename: Keith R
authors.initials: KR
authors.lastname: Neal
authors.affiliation: Health Protection Agency, Meningococcal Reference Unit, Manchester Royal Infirmary, Manchester M13 9WL, UK.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Gray
authors.affiliation: National Reference Laboratory for Meningococcal Infections, National Institute of Public Health, Prague, Czech Republic.
authors.forename: Paula
authors.initials: P
authors.lastname: Kriz
authors.affiliation: Molecular Bacteriology and Immunology Group, University of Nottingham, Nottingham, UK.
authors.forename: David P J
authors.initials: DPJ
authors.lastname: Turner
authors.affiliation: Molecular Bacteriology and Immunology Group, University of Nottingham, Nottingham, UK.
authors.forename: Dlawer A A
authors.initials: DAA
authors.lastname: Ala'Aldeen
authors.affiliation: The Department of Zoology, University of Oxford, South Parks Road, Oxford OX1 3SY, UK.
authors.forename: Martin C J
authors.initials: MCJ
authors.lastname: Maiden
authors.affiliation: Department of Genetics, University of Leicester, Leicester LE1 7RH, UK.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Bayliss
authors.forename: J G
authors.initials: JG
authors.lastname: Shaw
mesh_terms: D001425:Bacterial Outer Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D002353:Carrier State / Q000382:microbiology; D015964:Gene Expression Regulation, Bacterial; D007501:Iron / Q000378:metabolism; D008589:Meningococcal Infections / Q000382:microbiology*; D008969:Molecular Sequence Data; D009345:Neisseria meningitidis / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism* / Q000472:pathogenicity*; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D014774:Virulence
chemical_list: D001425:Bacterial Outer Membrane Proteins; D001426:Bacterial Proteins; C094109:HmbR protein, Neisseria meningitidis; C445303:HpuA protein, Neisseria; C105625:HpuB protein, Neisseria; D011956:Receptors, Cell Surface; D007501:Iron