Neisseria meningitidis GNA2132, a heparin-binding protein that induces protective immunity in humans

Abstract

GNA2132 is a Neisseria meningitidis antigen of unknown function, discovered by reverse vaccinology, which has been shown to induce bactericidal antibodies in animal models. Here we show that this antigen induces protective immunity in humans and it is recognized by sera of patients after meningococcal disease. The protein binds heparin in vitro through an Arg-rich region and this property correlates with increased survival of the unencapsulated bacterium in human serum. Furthermore, two proteases, the meningococcal NalP and human lactoferrin, cleave the protein upstream and downstream from the Arg-rich region, respectively. We conclude that GNA2132 is an important protective antigen of N. meningitidis and we propose to rename it, N eisserial H eparin B inding A ntigen (NHBA).

Neisseria meningitidis NalP cleaves human complement C3, facilitating degradation of C3b and survival in human serum

“…S1). NalP is a surface-exposed autotransporter with serine protease activity able to cleave different surface-exposed proteins, including Iga, NHBA, AusI, App, and LbpB (15,16,20,21). To determine whether NalP contributed to Nm survival in blood through an indirect effect by cleaving one or more of the known target proteins, deletion mutants of each NalP target were generated individually in strain MC58.…”

“…NalP contains a lipobox at the C-terminal end of the signal sequence; the lipid moiety permits anchorage in the outer membrane (16). Lipidated NalP proteins are only temporarily retained at the cell surface; however, the lipid moiety retards the release of NalP passenger domain from the bacterial surface and allows the partial or total cleavage of surface protein targets on bacterial surface (18), including IgA protease Iga, adhesion and penetration protein App (16), autotransporter serine protease AusI (19), Neisserial heparin binding antigen NHBA (20), and lactoferrin binding protein LbpB (21). This activity modulates the expression of meningococcal proteins at bacterial surface and also has recently been implicated in the formation and regulation of Nm biofilm (22).…”

Competence-induced protein Ccs4 facilitates pneumococcal invasion into brain tissue and virulence in meningitis

“…The glycosaminoglycans heparin and heparan sulfate contain similar structural units. Binding of heparin via an arginine-rich region is a characteristic of Neisseria meningitidis strain GNA2132 [18]. Although Ccs4 also possesses an arginine-rich region, our results suggest that it does not bind heparin.…”

“…GNA2132, a surface-exposed protein of Neisseria meningitidis , has been reported to possess an arginine-rich region (- R F RR SA R S RR S-), which promotes bacterial survival in human serum by binding with heparin [18]. Streptococcus agalactiae penetrates the BBB via interactions between bacterial surface alpha C protein and host surface heparan sulfate chains [19].…”

Bexsero

“…NHBA, formerly GNA2132, is a lipoprotein that appears to increase survival of N. meningitidis by binding glycosaminoglycans, 53 although its role in vivo requires further characterization. This antigen induces a bactericidal response in mice that is also protective by passive immunization in the infant rat model.…”