Distribution and diversity of the haemoglobin–haptoglobin iron-acquisition systems in pathogenic and non-pathogenic Neisseria

Abstract

A new generation of vaccines containing multiple protein components that aim to provide broad protection against serogroup B meningococci has been developed. One candidate, 4CMenB (4 Component MenB), has been approved by the European Medicines Agency, but is predicted to provide at most 70–80 % strain coverage; hence there is a need for second-generation vaccines that achieve higher levels of coverage. Prior knowledge of the diversity of potential protein vaccine components is a key step in vaccine design. A number of iron import systems have been targeted in meningococcal vaccine development, including the HmbR and HpuAB outer-membrane proteins, which mediate the utilization of haemoglobin or haemoglobin–haptoglobin complexes as iron sources. While the genetic diversity of HmbR has been described, little is known of the diversity of HpuAB. Using whole genome sequences deposited in a Bacterial Isolate Genome Sequence Database (BIGSDB), the prevalence and diversity of HpuAB among Neisseria were investigated. HpuAB was widely present in a range of Neisseria species whereas HmbR was mainly limited to the pathogenic species Neisseria meningitidis and Neisseria gonorrhoeae. Patterns of sequence variation in sequences from HpuAB proteins were suggestive of recombination and diversifying selection consistent with strong immune selection. HpuAB was subject to repeat-mediated phase variation in pathogenic Neisseria and the closely related non-pathogenic Neisseria species Neisseria lactamica and Neisseria polysaccharea but not in the majority of other commensal Neisseria species. These findings are consistent with HpuAB being subject to frequent genetic transfer potentially limiting the efficacy of this receptor as a vaccine candidate.

Heme Synthesis and Acquisition in Bacterial Pathogens

“…While not all N. meningitidis strains express both the HmbR and HpuAB systems, most express at least one. Most pathogenic isolates express at least HmbR, but HpuAB expression is equally associated with disease and carriage isolates, which indicates that HmbR is an indicator of pathogenesis [206,207]. N. meningitidis serotype B isolates associated with disease also exhibit “on” phase variation of HmbR, correlating virulence with the expression of HmbR [208].…”

The genes that encode the gonococcal transferrin binding proteins, TbpB and TbpA, are differentially regulated by MisR under iron‐replete and iron‐depleted conditions

“…Additionally, MisR regulation at the gonococcal tbpBA promoter described in this report is reminiscent of MisR regulation of the hemO ‐ hmbR hemoglobin receptor locus in meningococci (Zhao et al ., ). While gonococci are thought to primarily use the HpuBA hemoglobin receptor (Cornelissen and Hollander, ) and seem to encode only pseudogenes for hmbR (Harrison et al ., ) the striking parallels between these two regulatory schemes suggest that pathogenic Neisseriae may deploy both Fur and MisR to balance their nutritional requirements for iron and their need to limit oxidative damage and the presentation of conserved antigens. In agreement with this hypothesis, misR mutant meningococci were more sensitive to oxidative stress (Tzeng et al ., ) and generated broad, cross‐reactive immunity in an intraperitoneal mouse model of infection (Newcombe et al ., ).…”

Investigation into the Antigenic Properties and Contributions to Growth in Blood of the Meningococcal Haemoglobin Receptors, HpuAB and HmbR

“…The presence of variable regions in the surface-exposed components of the Hb receptors indicates that immune responses against these receptors exert a strong selection for antigenic variation [ 28 , 61 ]. Both receptors were immunogenic in mice and elicited antibodies that bound to surface-exposed regions of the proteins in whole cells as detected by FACs.…”