The meningococcal vaccine antigen GNA2091 is an analogue of YraP and plays key roles in outer membrane stability and virulence

Seib, K. L. et al. (2019) The meningococcal vaccine antigen GNA2091 is an analogue of YraP and plays key roles in outer membrane stability and virulence. FASEB Journal, 33(11), pp. 12324-12335. (doi: 10.1096/fj.201900669R) (PMID:31442078)

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Abstract

GNA2091 is one of the components of the 4-component meningococcal serogroup B vaccine (4CMenB) vaccine and is highly conserved in all meningococcal strains. However, its functional role has not been fully characterized. Here we show that nmb2091 is part of an operon and is cotranscribed with the nmb2089, nmb2090, and nmb2092 adjacent genes, and a similar but reduced operon arrangement is conserved in many other gram-negative bacteria. Deletion of the nmb2091 gene causes an aggregative phenotype with a mild defect in cell separation; differences in the outer membrane composition and phospholipid profile, in particular in the phosphoethanolamine levels; an increased level of outer membrane vesicles; and deregulation of the zinc-responsive genes such as znuD. Finally, the ∆2091 strain is attenuated with respect to the wild-type strain in competitive index experiments in the infant rat model of meningococcal infection. Altogether these data suggest that GNA2091 plays important roles in outer membrane architecture, biogenesis, homeostasis, and in meningococcal survival in vivo, and a model for its role is discussed. These findings highlight the importance of GNA2091 as a vaccine component.—Seib, K. L., Haag, A. F., Oriente, F., Fantappiè, L., Borghi, S., Semchenko, E. A., Schulz, B. L., Ferlicca, F., Taddei, A. R., Giuliani, M. M., Pizza, M., Delany, I. The meningococcal vaccine antigen GNA2091 is an analogue of YraP and plays key roles in outer membrane stability and virulence. Neisseria meningitidis, a gram-negative β-proteobacteria, is a leading cause of bacterial sepsis and meningitis worldwide (1). The meningococcal protein Genome-derived Neisseria Antigen 2091 (GNA2091) was first described during the N. meningitidis serogroup B reverse vaccinology project as a lipoprotein predicted to be surface exposed in some meningococcal strains, which is able to induce passive protection in the adult mouse model of meningococcal bacteraemia (2). The function of GNA2091 is still unknown, but because of its protective properties, it was selected for inclusion in the 4-component meningococcal serogroup B vaccine (4CMenB; trade name Bexsero) (3). The 4CMenB vaccine is widely licensed and used to protect against invasive meningococcal disease from MenB and has also been introduced in the United Kingdom for mass vaccination of infants (4). 4CMenB contains 3 recombinant proteins [factor H binding protein (fHbp), Neisseria heparin binding antigen (NHBA), and Neisserial adhesin A] and outer membrane vesicles (OMVs) derived from New Zealand strain NZ 98/254 (2, 5). The immunogenicity and stability of the recombinant antigens was optimized by generating protein-protein fusions of fHbp-GNA2091 and NHBA-GNA1030, which induce higher serum bactericidal activity titers than those induced by the individual antigens alone (2). fHbp, Neisserial adhesin A, and NHBA have been extensively characterized and shown to be involved in meningococcal virulence (6–11). The accessory protein GNA1030 has recently been characterized as a Neisseria ubiquinone binding protein (NUbp) (12). However, the role of GNA2091 has not yet been characterized in detail. GNA2091 has been shown to be localized at the periplasmic side of the outer membrane, where it is proposed to be required for the efficient assembly of a subset of outer membrane proteins (OMPs), including porin (Por)A, PorB, pili associated protein Q (PilQ), and the β-barrel assembly machinery (Bam) complex, with accumulation of misassembled monomeric proteins seen in a gna2091 mutant strain (13). The gna2091 mutant is also sensitive to detergent stress, indicating compromised membrane integrity (14). Here we further characterize the expression and functional role of GNA2091 in vitro and in the in vivo infant rat model of meningococcal bacteraemia.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Haag, Dr Andreas
Authors: Seib, K. L., Haag, A. F., Oriente, F., Fantappiè, L., Borghi, S., Semchenko, E. A., Schulz, B. L., Ferlicca, F., Taddei, A. R., Giuliani, M. M., Pizza, M., and Delany, I.
College/School:College of Medical Veterinary and Life Sciences > School of Infection & Immunity
Journal Name:FASEB Journal
Publisher:Federation of American Society of Experimental Biology
ISSN:0892-6638
ISSN (Online):1530-6860
Published Online:01 November 2019

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