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Casellato, Alessandro (2013) C2 Fragment from Neisseria meningitidis Antigen NHBA Disassembles Adherence Junctions of Brain Microvascular Endothelial Cells. [Tesi di dottorato]

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Abstract (inglese)

Neisseria meningitidis is the major cause of meningitis and sepsis, two kind of diseases that can affect children and young adults within a few hours, unless a rapid antibiotic therapy is provided. The meningococcal disease dates back to the 16th century. The first description of the disease caused by this pathogen was stated by Viesseux in 1805 as 33 deaths occurred in Geneva, Switzerland [1].
It took about seventy years before two Italians (Marchiafava and Celli) in 1884 identified micrococcal infiltrates within the cerebrospinal fluid [2].
The worldwide presence of meningococcal serogroups may vary within regions and countries.
With the coming of antimicrobial agents, like sulphonamides, and with the development of an appropriate health care and prevention programme, the fatality rate cases has dropped from 14% to 9%, although 11% to 19% of patients continued to have post-infection issues such as neurological disorders, hearing or limb loss [3].
The bacteria can be divided into 13 different serogroups and, among these, up to 99% of infection is ascribed to the serogroups named A, B, C, 29E, W-135 and Y (Fig. 2). All the serogroups have been listed in 20 serotypes on the presence of PorB antigen, 10 serotypes on the presence of PorA antigen, and in other immunotypes on the presence of other bacterial proteins and on the presence of a characteristic lipopolysaccharide called LOS (lipooligosaccharide) [4].
The transmission from a carrier to an other person occurs by liquid droplet and the natural reservoir of Neisseria meningitidis is the human throat, in particular it usually invades the human nasopharynx where it can survive asymptomatically.
The reported annual incidence goes from 1 to 5 cases per 100000 inhabitants in industrialized countries, while in non developed-countries the incidence goes up to 50 cases per 100000 inhabitants. More then 50% of cases occur within children below 5 years of age, and the peak regards those under the first year of age. This fact is due to the loss of maternal antibodies by the newborn. In non-epidemic period, the percentage of healthy carriers range from 10 to 20%, and notably the condition of chronic carrier is not so uncommon [5, 6]. Only in a small percentage of cases the colonization progresses until the insurgence of the pathogenesis. This happens because in the majority of cases specific antibodies or the human complement system are able to destroy the pathogens in the blood flow allowing a powerful impairment of the dissemination.
In a small group of population the colonization of the upper respiratory tract is followed by a rapid invasion of the epithelial cells, and from there bacteria can reach the blood flow and invade the central nervous system (CNS), inducing the establishment of an acute inflammatory response.
How the balance between being an healthy carrier or a infected patient can change so rapidly it is still unknown. Some factors that can play a role in this switch could be the virulence of the bacterial strain, the responsiveness of the host immune system, the mucosal integrity, and some environmental factors [7].
Neisserial heparin binding antigen (NHBA) is a surface- exposed lipoprotein from Neisseria meningitidis that was originally identified by reverse vaccinology [8].
NHBA in Nm has a predicted molecular weight of 51 kDa. The protein contains an Arg-rich region (-RFRRSARSRRS-) located at position 296–305 that is highly conserved among different Nm strains. The protein is specific for Neisseria species, as no homologous proteins were found in non redundant prokaryotic databases.
Full length NHBA can be cleaved by two different proteases in two different manners: NalP, a neisserial protein with serine protease activity cleaves the entire protein at its C-terminal producing a 22 kDa protein fragment (commonly named C2) which starts with Ser293 and hence comprises the highly conserved Arg-rich region. The human proteases lactoferrin (hLf) cleaves NHBA immediately downstream of the Arg-rich region releasing a shorter fragment of approximately 21 kDa (commonly named C1) [9] .
Although it is known that a crucial step in the pathogenesis of bacterial meningitidis is the disturbance of cerebral microvascular endothelial function, resulting in blood-brain barrier breakdown, the bacterial factor(s) produced by Nm responsible for this alteration remains to be established. The integrity of the endothelia is controlled by the protein VE-cadherin, mainly localized at cell-to-cell adherens junctions where it promotes cell adhesion and controls endothelial permeability [10]. It has been reported that alteration in the endothelial permeability can be ascribed to phosphorylation events induced by soluble factors such as VEGF or TGF-beta[11] [12].
Our work demonstrates that the NHBA- derived fragment C2 (but not C1) increases the endothelial permeability of HBMEC (human brain microvasculature endothelial cells) grown as monolayer onto the membrane of a transwell system. Indeed, the exposure of the apical domain of the endothelium to C2 allows the passage of the fluorescent tracer BSA-FITC, from the apical side to the basal one, early after the treatment. Interestingly, the effect of C2 on the endothelium integrity is such to allow the passage of bacteria, E. coli but, notably, also N. meningitidis MC58, from the apical to the basolateral side of the transwell and it depends on the production of mitochondrial ROS. Remarkably, we have found that the administration of C2 to endothelia results in a ROS-dependent reduction of the total VE-cadherin content. This event requires after VE-cadherin phosphorylation, the endocytosis and the subsequent degradation of the protein.
Collectively our data suggest the possibility that C2 might be involved in the mechanisms of invasion owned by the bacterium to cross host tissues.

Abstract (italiano)

Neisseria meningitidis è uno dei patogeni in grado di causare meningite oltre che sepsi in soggetti infettati, due patologie che colpiscono maggiormente bambini e adolescenti entro poche ore dal contagio a meno di una tempestiva terapia antibiotica. La malattia meningococcica risale al sedicesimo secolo. La prima descrizione della malattia causata da questo agente patogeno avvenne ad opera di Viesseux nel 1805 come conseguenza di 33 decessi occorsi a Ginevra, Svizzera [1].
Circa 70 anni dopo, due italiani (Marchiafava e Celli) nel 1884 identificarono per la prima volta degli infiltrati meningococcichi nel fluido cerebrospinale [2].
La presenza di Neisseria meningitidis nel mondo varia in base a paesi e regioni e risulta essere ciclica. Grazie alla scoperta di agenti antimicrobicidi come i sulfonamidici e grazie alla diffusione di un adeguato protocollo di prevenzione sanitaria i casi di mortalita` dovuti a questo agente patogeno sono rapidamente diminuiti dal 14 al 9%. Ciò nonostante una percentuale compresa tra l’11 e il 19% dei soggetti ha continuato ad avere problemi post-infezione come disordini neurologici, o perdità dell’udito [3].
Esistono attualmente 13 sierogruppi e, di questi, il 99% delle infezioni è causato dai tipi A, B, C, 29E, W-135 e Y.
I sierogruppi sono stati a loro volta classificati in 20 sierotipi sulla base della presenza dell’antigene proteico PorB, in 10 sierotipi sulla base dell’antigene PorA e in altri immunotipi a seconda della loro capacita` di indurre una risposta immunitaria nell’ospite grazie alla presenza di altre proteine batteriche del patogeno, e per la presenza di un particolare lipopolisaccaride chiamato LOS (lipooligosaccaride) [4].
Neisseria meningitidis è in grado di colonizzare l’epitelio della mucosa orofaringea, dove vi può sopravvivere in maniera asintomatica per l’ospite.
La trasmissione inter-individuale avviene attraverso secrezioni dell’apparato respiratorio. L’ incidenza annuale risulta essere di 1- 5 casi ogni 100000 abitanti nei paesi industrializzati, mentre nei paesi ancora in via di sviluppo questa sale a 50 casi per 100000 abitanti. Più del 50% dei casi riguarda bambini sotto i 5 anni d’età, con un’elevata incidenza per coloro che hanno meno di un anno di vita. Questo fatto dipende dall’emivita degli anticorpi materni solitamente in grado di proteggere il neonato per circa 3-4 mesi dopo la nascita. In periodi definiti non-epidemici la percentuale dei portatori sani varia tra il 10 e il 20% della popolazione, e per l’appunto la condizione di portatore asintomatico non è poi così infrequente [5, 6]. Soltanto in un numero ristretto di casi la colonizzazione del batterio progredisce manifestando la patogenesi meningococcica: ciò è per la maggior parte dovuto alla presenza di specifici anticorpi, o per l’attività del sistema del complemento dell’ospite che è in grado di controllare ed eliminare il patogeno impedendone così la sua disseminazione attraverso il flusso sanguigno.
Tuttavia, in un piccolo gruppo della popolazione, la colonizzazione del tratto respiratorio superiore è seguita da una rapida invasione delle cellule epiteliali della mucosa, da dove il batterio è in grado di entrare nel torrente ematico, e raggiungere il sistema nervoso centrale inducendo una forte risposta infiammatoria.
Quale sia l’evento che perturbi l’equilibrio tra essere portatore asintomatico e paziente infetto ancora non è noto. Alcuni fattori sembrano giocare un ruolo chiave in questo cambiamento come la virulenza del ceppo batterico, la capacità della risposta immunitaria dell’ospite, l’integrità della mucosa e alcuni fattori ambientali [7].
La proteina NHBA, Neisserial Heparin Binding Antigen, è una lipoproteina esposta sulla superficie del batterio, originariamente identificata attraverso la tecnica della “reverse vaccinology” [8].
NHBA in Nm ha un peso molecolare predetto di 51 kDa. La proteina altresì contiene una regione ricca in Arginine (-RFRRSARSRRS-) localizzata in posizione 296 -305 ed altamente conservata in vari ceppi di Neisseria [9]. Tale proteina è altamente conservata in Neisseria e non ha omologie di sequenza con nessun’altra proteina registrata nei database procariotici.
Due diverse proteasi possono tagliare la proteina intera NHBA producendo due frammenti differenti: nel primo caso la proteasi batterica NalP taglia la proteina intera in posizione C-terminale producendo un frammento di 22 kDa (comunemente chiamato C2) che inzia con la Ser293 e quindi comprendendo lo stretch di Arginine. Invece, nel secondo caso, la lattoferrina umana (hLf) taglia NHBA immediatamente a monte della sequenza di Arginine, producendo un frammento più corto di circa 21 kDa (comunemente chiamato C1). Sebbene sia risaputo che un passaggio cruciale nella patogenesi mediata da Neisseria meningitidis sia l’alterazione della funzione di barriera della microvascolatura encefalica, che può dunque risultare in una rottura della barriera emato- encefalica stessa, non è ancora chiaro quali siano i fattori rilasciati o prodotti dal batterio in grado di indurre un simile effetto. L’integrità dell’endotelio è controllata dalla proteina VE-caderina, localizzata sulle giunzioni aderenti che regolano il contatto cellula- cellula. Tale proteina promuove e regola dunque la permeabilità endoteliale [10]. E’ stato ben documentato che l’alterazione della permeabilità endoteliale può essere dovuta a processi di fosforilazione indotti da fattori solubili come VEGF o TGF-beta[11] [12].
Il nostro lavoro documenta come, a differenza del frammento C1, il frammento C2 prodotto dal taglio della proteina intera NHBA, sia in grado di aumentare la permeabilità delle cellule endoteliali HBMEC (human brain microvasculature endothelial cells) fatte crescere a monostrato sulla membrana di un sistema di transwell. L’esposizione della porzione apicale dell’endotelio polarizzato al frammento C2 consente il passaggio di un tracciante fluorescente, BSA-FITC, dal lato superiore a quello inferiore del transwell, in tempi rapidi a seguito del trattamento. E’ interessante notare che l’effetto di C2 sull’endotelio è tale da permettere il passaggio dal lato superiore a quello inferiore del transwell non solo di E. coli, usato come modello batterico preliminare, ma anche dello stesso Neisseria meningitidis MC58, in maniera ROS dipendente. Degno di nota è il fatto che abbiamo osservato che la somministrazione di C2 alle cellule endoteliali provoca una riduzione ROS dipendente del contenuto totale di VE-caderina. A seguito della sua fosforilazione, infatti, VE-caderina viene endocitata all’interno della cellula per poi essere degradata probabilmente attraverso il trasporto di essa verso il proteasoma.
I nostri dati suggeriscono pertanto che C2 sia uno dei meccanismi di invasione possieduti da Neisseria per invadere i tessuti dell'ospite.

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Tipo di EPrint:Tesi di dottorato
Relatore:De Bernard, Marina
Dottorato (corsi e scuole):Ciclo 25 > Scuole 25 > BIOSCIENZE E BIOTECNOLOGIE > BIOLOGIA CELLULARE
Data di deposito della tesi:28 Gennaio 2013
Anno di Pubblicazione:28 Gennaio 2013
Parole chiave (italiano / inglese):Neisseria meningitidis; NHBA; Ve-cadherin;Endothelial cells;
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/11 Biologia molecolare
Struttura di riferimento:Dipartimenti > Dipartimento di Biologia
Codice ID:5561
Depositato il:25 Ott 2013 11:27
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