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Spadafina, Tiziana (2009) Characterization of Neisseria meningitidis GNA2132 antigen, a heparin binding protein cleaved by meningococcal NalP protease. [Tesi di dottorato]

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Abstract (inglese)

ABSTRACT

GNA2132 (Genome-derived Neisseria Antigen 2132), a protein discovered by Reverse Vaccinology, is a surface-exposed lipoprotein expressed by genetically diverse Neisseria meningitidis strains. The protein induces bactericidal antibodies against most strains of meningococccus and has been included in a multivalent recombinant vaccine against N. meningitidis serogroup B. Sequence analysis of GNA2132 revealed the presence of an Arginine-rich region highly conserved among different strains.
In this study we described that in meningococcus the protein is cleaved upstream from the Arginine-rich region and the C-terminal fragment is released in the culture supernatant.
By genetic approaches we demonstrated that the processing of GNA2132 is strain-dependent and correlates with the expression of NalP, a phase variable autotransporter with a serine-protease activity, which has been previously shown to cleave known Neisseria virulence factors.
Sequence analysis of GNA2132 protein revealed the presence of an Arginine-rich region highly conserved among N. meningitidis strains. Our functional studies revealed that this region is crucial for the function of GNA2132 since recombinant GNA2132 binds heparin through the Arginine-rich region motif.

Abstract (italiano)

RIASSUNTO

GNA2132 (Genome-derived Neisseria Antigen 2132), una proteina scoperta tramite la Reverse Vaccinology, è una lipoproteina esposta sulla membrana esterna di Neisseria meningitidis. La proteina è in grado di indurre anticorpi battericidi contro la maggior parte dei ceppi di meningococco e per questa ragione è stata inclusa da Novartis nel vaccino contro meningococco serogruppo B. In questo studio abbiamo descritto come in meningococco GNA2132 è tagliata appena prima della regione ricca in arginine ed un frammento corrispondente alla porzione C-terminale della proteina è rilasciato nel supernatante di coltura.
Tramite un approccio genetico abbiamo dimostrato che il taglio di GNA2132 è un processo ceppo-dipendente. Inoltre abbiamo dimostrato che il processamento di GNA2132 correla con l’espressione di NalP, un autotransporter ad attività serino-proteasica, la cui espressione subisce variazione di fase e che è in grado di modulare il processamento di altri fattori di virulenza di meningococco.
GNA2132 contiene una regione ricca in arginine che analisi di sequenza hanno dimostrato essere altamente conservata in moltissimi ceppi di meningococco. I nostri studi sulla funzione della GNA2132 e dei frammenti generati indicano che la GNA2132 è capace di legare l’eparina e mostrano come questa regione sia fondamentale nel legame: infatti il frammento privo della regione ricca in arginine e le proteine ricombinanti (priva della zona in arginine oppure mutata nelle arginine) non mostrano avere il fenotipo di legame all’eparina.

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Tipo di EPrint:Tesi di dottorato
Relatore:Montecucco, Cesare
Dottorato (corsi e scuole):Ciclo 21 > Scuole per il 21simo ciclo > BIOSCIENZE > BIOLOGIA CELLULARE
Data di deposito della tesi:29 Gennaio 2009
Anno di Pubblicazione:30 Gennaio 2009
Parole chiave (italiano / inglese):neisseira meningitidis, antigen, vaccine, NalP, heparin binding protein
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/11 Biologia molecolare
Struttura di riferimento:Dipartimenti > pre 2012 - Dipartimento di Scienze Biomediche Sperimentali
Codice ID:1546
Depositato il:29 Gen 2009
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