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Compostella, Maria Elena (2016) Structural characterization of Helicobacter pylori proteins contributing to stomach colonization. [Tesi di dottorato]

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Abstract (inglese)

Helicobacter pylori is a well-characterizDe human pathogen that colonizes the stomach of more than half of the world’s population. It is a Gram-negative, microaerophilic, flagellated, spiral shaped bacterium able to establish a life‐long chronic infection in the gastric mucosa. Infection with H. pylori is generally acquired early in childhood, with a higher prevalence in developing countries, and typically persists for life. As in many chronic infections, most individuals remain asymptomatic with only a small proportion developing clinical disease. H. pylori is considered a pathogen as it universally causes progressive inflammation and gastric mucosal damage; in 1994 it was declared a class I human carcinogen by the World Health Organization (WHO). The clinical outcomes associated to H. pylori infection include severe gastroduodenal diseases, such as peptic and duodenal ulcers, noncardia gastric adenocarcinoma, and gastric mucosa-associated lymphoid tissue (MALT) lymphoma. For more than 100 years it has been recognized that atrophic gastritis was tightly associated with gastric cancer. The discovery of H. pylori in 1983 identified the cause of chronic gastric mucosal inflammation and thus the underlying cause of gastric cancer. As consequence, since its culture from a gastric biopsy, H. pylori has been the subject of intense investigations and provoked the interest of many scientists, such as bacteriologists, molecular biologist, gastroenterologists, infectious disease specialists, cancer biologists, epidemiologists, pathologists, and pharmaceutical scientists.
H. pylori has developed a surprising molecular machinery to survive in the unfriendly environment and achieve a successful colonization of the stomach. Since H. pylori is not an acidophilus bacterium, it has evolved several specialized mechanisms to survive gastric acid. The pathogen has to resist in the gastric lumen for a short period, enough to enter into the highly viscous mucosa, reach the gastric epithelium, find nutrients and multiply. Some acid-adaptive mechanisms include an acid-activated inner membrane urea channel, UreI, a neutral pH-optimum intrabacterial urease, and periplasmic and cytoplasmic carbonic anhydrases. This acid acclimation system allows to regulate the pH of the periplasm and of the surrounding liquid in acidic medium at levels compatible with survival and growth. A key factor essential for survival and successful colonization is the bacterial motility, mediated by its sheathed unipolar flagella, allowing H. pylori to swim in response to a gradient of pH and to stay within the mucus layer, where the pH is generally higher with respect to the lumen. Approximately only 20% of H. pylori bacteria in the stomach adhere to the surface of the gastric epithelial cells; bacterial adhesion involves specialized molecular interactions mediated by adhesins and surface components, which are able to evade the host immune recognition by displaying a high antigenic variation. H. pylori is characterized by high genetic variability, not only in gene sequence but also in gene content, evidenced by the availability of complete genome sequences. One of the most striking differences in H. pylori strains is the presence or absence of a 40‐kb DNA region named cag Pathogenicity Island, that encodes a Type IV Secretion System, causing the translocation of CagA toxin, one of the most relevant virulence factor of H. pylori. Upon injection into epithelial gastric cells, CagA induces cellular modifications, including alteration of cell structure, motility, cell scattering and proliferation, and tight junctions. A further relevant virulence factor is the vacuolating cytotoxin VacA, which is a secreted, pore-forming toxin able to induce vacuolization in gastric epithelial cells. Almost all H. pylori strains contain a vacA gene, but the gene sequence is highly variable, causing changes in VacA virulence activity. Therefore, H. pylori strains can be classified in subtypes associated with different levels of pathogenic offense during colonization, on the basis of the variability of the virulence factors. However, the various and divergent clinical outcomes deriving from the H. pylori infection are dictated by a complex balance between host genetic factors, bacterial virulence determinants, and environmental components. Therefore, understand in detail the host-pathogen relationship is a complex challenge, still incomplete. Despite that the bacterial genome has been completely sequenced, several pathogenic mechanisms have not yet been defined. Moreover, currently H. pylori can be eradicated by a triple therapy combining a protonic pump inhibitor and antibiotics; but the increasing antibiotic resistance is the main reason for this treatment failure. Therefore, it becomes necessary to identify new pharmacological targets against the bacterium, in order to overcome the serious problem of the drug-resistance and to develop new antibiotic treatments.
The main purpose of this research project is focused on identification and structural characterization of new potential pharmacological targets of H. pylori. In this respect, proteins responsible for colonization and virulence, as well as secreted proteins mediating important pathogen-host interactions, are interesting candidates for structural characterization, in order to deepen their putative function. In particular, the investigations were focused on the periplasmic α-carbonic anhydrase (HPG27_1129), the cytoplasmic β-carbonic anhydrase (HPG27_4), the flagellar protein FliK (HPG27_857), the thiol: disulfide oxidoreductase HPG27_1020, and two secreted “hypothetical proteins”, namely HPG27_1030 and HPG27_1117.
The research described in this thesis was mostly carried out at the Department of Biomedical Sciences, University of Padova, and at Venetian Institute of Molecular Medicine (VIMM), Padova. The strategy adopted included preliminary bioinformatic analyses, PCR-amplification of the selected genes starting from purified H. pylori chromosomal DNA (strain G27), cloning in a His-tag-containing vector and expression of the protein in E. coli competent cells. The recombinant proteins were then purified using two chromatography steps, from soluble or insoluble fractions, and concentrated for crystallization trials. The α-carbonic anhydrase was successfully crystallized and the structure was determined by x-ray diffraction. Crystals of β-carbonic anhydrase and HPG27_1117 were also obtained, nevertheless not suitable to x-ray diffraction measurement. To ensure the sample quality, Western blotting, analytical gel-filtration, UV-Vis absorption spectrum, circular dichroism analyzes were performed.
Structural peculiarities and possible functional implications of α-carbonic anhydrase are described in Chapter III. This periplasmic protein plays a key role in the complex balance of urea and bicarbonate aimed to the survival in the stomach, catalyzing the reversible conversion of carbon dioxide to bicarbonate; thus, it is fundamental in buffering the pH of the periplasm. H. pylori α-carbonic anhydrase was cloned as recombinant protein lacking the N-terminal secretion signal, expressed in E. coli cells and purified; crystals were obtained by vapor-diffusion technique and the structure was determined at 1.52 Å by molecular replacement, based on a model built from α-carbonic anhydrase from Sulfurihydrogenibium yellowstonense (Di Fiore et al., 2013; PDB accession code: 4G7A). The protein structure shares many features with other members of the α-carbonic anhydrase family, showing a central ten-stranded β-sheet surrounded by three α-helices and by the remainder of the protein chain. Structural peculiarities are presented by the active site, since the glutamic acid residue (position 127) interacting with three catalytic histidine residues is substituted by a serine residue and the absent negative charge is replaced by a chloride ion captured from the external medium. The definition of the structural details of the protein allows to investigate new specific inhibitors as potential antibiotics against H. pylori. Moreover, cocrystallization trials were performed to investigate the molecular binding of inhibitor compounds to the active site; but cocrystals suitable to x-ray diffraction measurement have not been obtained yet.
The pathogen encodes a further carbonic anhydrase, namely the cytoplasmic β-carbonic anhydrase, whose investigations are described in Chapter IV. The enzyme is hypothesized to catalyze the same conversion for the carbon dioxide molecules that do not freely diffuse out of the inner membrane, contributing to buffer the pH of the cytoplasm and survival in the gastric acid environment. The β-carbonic anhydrase was cloned as 6-His-tag recombinant protein and expressed in E. coli competent cells, exhibiting a limited yield of soluble protein, the most relevant limit encountered, likely owing to an improper folding by E. coli cells. The purification was performed both from the soluble and from the insoluble fractions, adopting various chromatographic techniques. Higher quality protein sample was obtained via immobilized-metal ion affinity chromatography, although the final yield of purified protein was impaired by the low affinity for the Ni-NTA resin. The purified protein was concentrated for crystallization trials, but crystals obtained were not suitable to x-ray diffraction measurement.
In Chapter V the investigations on the flagellar protein FliK are reported. As mentioned before, bacterial motility mediated by unipolar flagella is an essential factor to minimize the exposure to the acid environment and to achieve a successful colonization of the gastric mucosa. In H. pylori more than 50 putative proteins are predicted to be involved in expression, secretion and assembly of the flagellar apparatus. It is composed of three structural elements: a basal body, an external helically shaped filament, and a hook that serves as a joint. FliK is responsible for the hook length control and in fliK mutants it has been observed that long hooks of unregulated length, named polyhooks, are formed, impairing the bacterial motility. Preliminary bioinformatics analyzes have evidenced that the flagellar protein exhibits an overall unstructured nature, with a limited folded region located at the C-terminal domain. Flik was cloned as 6-His-tag recombinant protein and several expression attempts were performed, adopting various E. coli strains and varying the conditions. Nevertheless, FliK exhibited an improper production by E. coli cells and degradation processes, likely ascribed to the high disorder level of the sequence. Strategies to overcome the limits of successful expression could be the cloning as single domains, or selecting more sophisticated system of expression, able to properly fold the protein.
Since the formation of disulfide bonds plays a key role also in bacterial virulence, many bacteria possess an oxidative protein-folding machinery to properly assemble their proteins, including H. pylori. The thiol:disulfide oxidoreductase HPG27_1020, whose experimental procedures are reported in Chapter VI, is a thioredoxin-fold protein which plays a role in the cytochrome c maturation, as well as in oxidized protein proper folding. Therefore, it provides essential function in H. pylori and represents a possible pharmacological target. Since its N-terminal region encode an export signal, the protein was cloned as 6-His-tag recombinant protein lacking of 24 N-terminal aminoacids. The recombinant HPG27_1020 protein was successfully expressed in E. coli cells, exhibiting a significant amount of soluble protein (approximately 60%). The researches were forcedly interrupted since meantime the x-ray structure of the thiol:disulfide oxidoreductase from H. pylori 26695, namely HP0377, has been determined and published. Their aminoacid sequences show a high degree of identity (96%), therefore the investigation has not longer been considered innovative.
In Chapter VII cloning, expression, purification and crystallization trials concerning two secreted “hypothetical proteins”, namely HPG27_1030 and HPG27_1117, are described. Recently, several secreted proteins were identified by proteomic analysis of H. pylori secretome; they represent attractive subjects of structural and functional investigations, since they could mediate important pathogen-host interactions and, thus, represent potential target for antibiotics and vaccine development. HPG27_1030 was successfully cloned as 6-His-tag recombinant protein, expressed in E. coli cells and purified by two chromatography steps. A significant amount of soluble purified protein was achieved, but the protein exhibited instability in solution and a clear tendency to aggregation, resulting in a limited final concentration of purified sample for crystallization trials. HPG27_1117 was cloned, expressed and purified as before. The most relevant limits encountered were the low yield of expression and the tendency to degradation. Nevertheless, purified protein was concentrated for crystallization trials and crystals were obtained by vapor-diffusion technique; but the crystals diffracted at a limited resolution and crystals suitable to x-ray diffraction measurement have not been obtained yet. To overcome the common problem of instability and degradation of these secreted proteins, changings in the buffer composition could improve the stability in solution and enhance the final yield of purified product for crystallization trials.
Concluding, identification of some new bacterial features have made possible to increase the overall knowledge about H. pylori and its peculiar mechanisms aimed to survival and virulence. On the basis of these findings, new investigations can be approached, in order to widely understand the pathophysiological mechanisms of this peculiar pathogen and to develop new eradication treatments.

Abstract (italiano)

Helicobacter pylori è un microorganismo patogeno ben caratterizzato, che colonizza lo stomaco di più di metà della popolazione mondiale. È un batterio Gram-negativo, microaerofilo, flagellato, spiraliforme, in grado di instaurare un’infezione cronica della mucosa gastrica, che può durare tutta la vita se non trattata. L’infezione da H. pylori è generalmente acquisita in età infantile, con un tasso di prevalenza maggiore nei paesi in via di sviluppo, e tipicamente persiste per tutto il corso della vita. Come nel caso di molte infezioni croniche, la maggior parte degli individui risulta asintomatica, mentre solo una limitata porzione sviluppa patologie correlate. H. pylori è considerato un microorganismo patogeno poiché causa universalmente un’infiammazione progressiva e danni tissutali alla mucosa gastrica; nello specifico, nel 1994 H. pylori è stato dichiarato un agente carcinogeno di classe I per l’uomo da parte della World Health Organization (WHO). Gli esiti clinici conseguenti all’infezione da H. pylori comprendono patologie gastrointestinali particolarmente severe, quali ulcere peptica e duodenale, adenocarcinoma gastrico non cardia e MALT linfoma (mucosa-associated lymphoid tissue lymphoma). Da più di 100 anni è riconosciuto che la gastrite atrofica è strettamente associata al cancro del tessuto gastrico. La scoperta dell’esistenza di H. pylori nel 1983 ha identificato la causa dell’infiammazione cronica della mucosa gastrica e quindi la causa fondamentale del cancro allo stomaco. Di conseguenza, sin dalla sua scoperta a partire da biopsie di tessuto gastrico, H. pylori è al centro di intense investigazioni e suscita l’interesse di molti studiosi, quali batteriologi, biologi molecolari, gastroenterologi, infettivologhi, biologi specializzati in patologie cancerose, epidemiologi, patologi e farmacologi.
Per sopravvivere nell’ambiente estremamente inospitale dello stomaco e potervi realizzare una colonizzazione efficace, H. pylori ha sviluppato una sorprendente macchina molecolare. Poiché non è un batterio acidofilo, H. pylori ha evoluto molti espedienti specializzati per sopravvivere all’acidità gastrica. Innanzitutto, il patogeno deve resistere alle condizioni estreme del lume gastrico solo per un breve periodo, sufficiente per penetrare nella mucosa altamente viscosa, raggiungere l’epitelio gastrico, recuperare nutrienti e moltiplicarsi. Alcuni dei meccanismi coinvolti nell’adattamento alle condizioni acide prevedono il canale per l’urea, UreI, localizzato nella membrana interna e attivato da un pH acido, l’ureasi citoplasmatica, caratterizzata da un optimum di attività a pH neutro, e due anidrasi carboniche, localizzate nel citoplasma e nel periplasma. Questo sistema di adattamento all’acidità gastrica permette di regolare il pH del periplasma e anche del liquido circostante nonostante l’ambiente acido, a livelli compatibili con la sopravvivenza e la crescita. Inoltre, un fattore cruciale per la sopravvivenza e una colonizzazione efficace del tessuto gastrico è rappresentato dalla motilità del batterio, resa possibile da flagelli unipolari e rivestiti da una guaina di difesa; grazie a quali H. pylori è in grado di nuotare in risposta a un gradiente di pH e di rimanere all’interno dello strato di muco gastrico, dove il pH è generalmente maggiore rispetto al lume dello stomaco. Circa solo il 20% dei microorganismi nello stomaco aderisce alla superfice delle cellule epiteliali gastriche; in particolare, l’adesione batterica vede coinvolte interazioni molecolari specializzate, mediate da adesine e altre componenti della superficie batterica, che sono in grado di eludere il riconoscimento da parte del sistema immunitario dell’ospite grazie a una elevata variabilità antigenica. Infatti, H. pylori è caratterizzato da una sorprendente variabilità genetica, non solo per quanto riguarda la sequenza dei geni, ma anche nel contenuto genico; la disponibilità delle sequenze genomiche complete ha reso possibile rilevare questa elevata variabilità in H. pylori. Soprattutto, una delle differenze più evidenti tra i ceppi di H. pylori è la presenza o meno di un frammento di DNA cromosomico di 40 kb chiamato isola di patogenicità cag, che codifica per un sistema di secrezione di tipo IV, responsabile della traslocazione della tossina CagA, uno dei più importanti fattori di virulenza di H. pylori. In seguito all’iniezione all’interno delle cellule epiteliali gastriche, CagA induce una serie di modificazioni cellulari, tra le quali alterazioni della struttura cellulare, della motilità, della proliferazione e della migrazione cellulari, della struttura delle giunzioni cellulari occludenti. Un ulteriore importante fattore di virulenza è la citotossina vacuolizzante VacA, che consiste in una tossina secreta, in grado di formare pori nelle membrane e indurre vacuolizzazione nelle cellule epiteliali gastriche. Quasi tutti i ceppi di H. pylori contengono il gene che codifica VacA, ma la sequenza genica è altamente variabile, causando perciò cambiamenti nell’intensità dell’attività di VacA. Perciò, in base alla variabilità dei fattori di virulenza, i ceppi di H. pylori possono essere classificati in sottotipi, ciascuno dei quali è associato a differenti livelli di patogenicità in seguito a colonizzazione. Oltre a quanto riportato, gli esiti clinici vari e divergenti derivanti dall’infezione da H. pylori dipendono da un intricato bilancio tra variabilità genetica dell’ospite, fattori di virulenza batterica e componenti ambientali. Perciò, la comprensione dettagliata della relazione tra ospite e patogeno è una sfida complessa, ancora da chiarire nella sua interezza. Nonostante che il genoma da più ceppi di H. pylori sia stato completamente sequenziato, molti dei meccanismi di patogenicità non sono ancora stati definiti. Inoltre, l’attuale trattamento di eradicazione di H. pylori prevede una tripla terapia che combina un inibitore di pompa protonica e due antibiotici; ma la crescente diffusione di antibiotico resistenza è il principale motivo del fallimento di questa terapia. Perciò si rende necessario identificare nuovi target farmacologici contro questo patogeno, al fine di superare il preoccupante problema della farmaco resistenza e di sviluppare nuovi trattamenti antibiotici.
Lo scopo principale di questo progetto di ricerca verte sull’identificazione e la caratterizzazione strutturale di nuovi potenziali target farmacologici di H. pylori. A questo proposito, proteine responsabili di colonizzazione e virulenza, così come proteine secrete che mediano le rilevanti interazioni tra ospite e patogeno, sono ritenute interessanti candidati per la caratterizzazione strutturale, allo scopo di approfondire la loro funzione presunta. In dettaglio, le indagini di questo progetto di ricerca si sono concentrate sull’α-anidrasi carbonica (HPG27_1129), con localizzazione periplasmatica, la β-anidrasi carbonica (HPG27_4), con localizzazione citoplasmatica, la proteina flagellare FliK (HPG27_857), l’ossidoreduttasi HPG27_1020 e infine due “proteine ipotetiche” secrete, di funzione sconosciuta, cioè HPG27_1030 e HPG27_1117.
Il lavoro di ricerca descritto in questa tesi è stato eseguito presso il Dipartimento di Scienze Biomediche dell’Università di Padova e presso l’Istituto Veneto di Medicina Molecolare (VIMM) di Padova. La strategia adottata prevedeva analisi bioinformatiche preliminari, amplificazione del gene di interesse tramite PCR a partire da DNA cromosomico purificato di H. pylori (ceppo G27), clonaggio in vettori in fusione con un 6-His-tag ed espressione in cellule competenti di E. coli. Di seguito, Le proteine ricombinanti sono state purificate tramite procedimenti che prevedono due passaggi cromatografici, sia dalla frazione solubile che da quella insolubile, e quindi concentrate per le prove di cristallizzazione. α-anidrasi carbonica è stata cristallizzata con successo e la struttura è stata determinata tramite diffrazione a raggi X. Inoltre, sono stati ottenuti cristalli anche di β-anidrasi carbonica e di HPG27_1117, però non adatti per la misura di dati di diffrazione a raggi X di buona risoluzione. Per assicurare la qualità del campione di proteina, sono state eseguite analisi quali Western blotting, gel-filtrazione analitica, spettro di assorbimento UV-Vis, spettro di dicroismo circolare.
Le peculiarità strutturali e le possibili implicazioni funzionali di α-anidrasi carbonica sono descritte nel Capitolo III. Questa proteina periplasmatica svolge un ruolo chiave nell’intricato bilancio di urea e bicarbonato volto alla sopravvivenza del batterio nello stomaco, poiché catalizza la conversione reversibile dell’anidride carbonica in bicarbonato; perciò, essa è fondamentale nel regolare il pH del periplasma, dove è localizzata. α-anidrasi carbonica da H. pylori è stata clonata come proteina ricombinante mancante del segnale N-terminale di secrezione, è stata espressa in cellule di E. coli e infine purificata; cristalli sono stati ottenuti mediante il metodo a diffusione di vapore e la struttura è stata determinata a 1.52 Å tramite molecular replacement, basandosi su un modello costruito a partire da α-anidrasi carbonica di Sulfurihydrogenibium yellowstonense (Di Fiore et al., 2013; codice PDB: 4G7A). La struttura della proteina condivide molte caratteristiche con altri membri della famiglia delle α-anidrasi carboniche, in quanto presenta un β-foglietto centrale costituito da 10 filamenti, circondato da 3 α-eliche e dalla rimanente catena polipeptidica. Alcune peculiarità strutturali sono presentate dal sito attivo, poiché il residuo di acido glutammico (posizione 127) che interagisce con i tre residui catalitici di istidina è sostituito da un residuo si serina nella stessa posizione e la carica negativa mancante è rimpiazzata da uno ione cloro catturato dal mezzo esterno. La determinazione dei dettagli strutturali di questa proteina permette di ricercare nuovi specifici inibitori che possano agire come potenziali antibiotici contro H. pylori. Inoltre, sono state eseguite delle prove di cocristallizzazione con inibitori sulfamidici, per investigare i dettagli strutturali delle interazioni dei composti inibitori col sito attivo; ma cocristalli di qualità adatta per la misura dei dati di diffrazione a raggi X non sono stati ancora ottenuti.
Il microorganismo patogeno codifica anche un’ulteriore anidrasi carbonica, cioè β-anidrasi carbonica localizzata nel citoplasma, le cui indagini sono descritte nel Capitolo IV. Si ipotizza che questo enzima catalizzi la stessa conversione per quanto riguarda le molecole di anidride carbonica che non diffondono liberamente al di fuori della membrana interna; perciò contribuisce alla regolazione del pH del citoplasma e alla sopravvivenza nell’ambiente gastrico estremamente acido. β-anidrasi carbonica è stata clonata come proteina ricombinante con un 6-His-tag ed espressa in cellule competenti di E. coli; però il principale limite incontrato è stato una limitata resa di proteina solubile, probabilmente dovuta a un’impropria organizzazione tridimensionale da parte delle cellule di E. coli. La purificazione è stata eseguita sia a partire dalla frazione solubile sia da quella insolubile, adottando tecniche cromatografiche variegate. Il campione di proteina di migliore qualità è stato ottenuto per mezzo della cromatografia di affinità per ioni metallici immobilizzati, sebbene la resa finale di proteina purificata sia stata compromessa a causa della moderata affinità per la resina Ni-NTA. La proteina purificata è stata concentrata per le prove di cristallizzazione, ma i cristalli ottenuti non sono di qualità adatta per la misura dei dati di diffrazione a raggi X.
Nel Capitolo V è riportato il lavoro di ricerca sulla proteina flagellare FliK. Come menzionato in precedenza, la motilità batterica mediata dai flagelli unipolari è un fattore essenziale per minimizzare il contatto con l’ambiente acido e realizzare una colonizzazione efficiente della mucosa gastrica. In H. pylori si prevede che più di 50 proteine siano coinvolte nell’espressione, secrezione e assemblaggio dell’apparato flagellare. Quest’ultimo è composto di tre elementi strutturali; un corpo basale, un filamento esterno a forma elicoidale e un uncino che serve ad unione. FliK è responsabile del controllo della lunghezza dell’uncino e si è osservato che in mutanti mancanti del gene di FliK si formano lunghi uncini di lunghezza incontrollata, chiamati “polyhooks”, che compromettono la motilità batterica. Analisi bioinformatiche preliminari hanno evidenziato come questa proteina flagellare presenti una struttura globale altamente disordinata, con una limitata regione strutturata localizzata a livello del dominio C-terminale. FliK è stata clonata come proteina ricombinante con un 6-His-tag e numerosi tentativi di espressione sono stati eseguiti, facendo uso di differenti ceppi di E. coli e variando le condizioni. Nonostante ciò, si sono riscontrati un’impropria produzione di FliK da parte delle cellule di E. coli e un’evidente degradazione della proteina, probabilmente entrambi gli eventi dovuti all’elevato grado di disordine della sequenza amminoacidica. Alcune strategie per risolvere questo limite dell’espressione potrebbero essere il clonaggio dei singoli domini oppure l’utilizzo di sistemi di espressione più sofisticati, in grado di strutturare correttamente la proteina.
Poiché la formazione dei ponti disolfuro riveste un ruolo chiave anche nella virulenza batterica, molti batteri posseggono sistemi molecolari per l’assemblaggio delle proteine nel corretto stato ossidativo, tra cui anche H. pylori. L’ossidoreduttasi HPG27_1020, le cui procedure sperimentali sono riportate in Capitolo VI, è una proteina con un’organizzazione simile alla tioredoxina che riveste un ruolo cruciale nella maturazione del citocromo c, così come nell’assemblaggio corretto di proteine ossidate. Perciò, questa proteina fornisce funzioni essenziali per H. pylori e rappresenta un possibile target farmacologico. Poiché la regione N-terminale codifica un segnale di secrezione, la proteina è stata clonata come proteina ricombinante con un 6-His-tag e mancante dei 24 amminoacidi N-terminali. HPG27_1020 ricombinante è stata espressa con successo in cellule di E. coli, mostrando una quantità significativa di proteina nella frazione solubile (circa il 60%). Però le ricerche sono state obbligatoriamente interrotte, in quanto nel frattempo è stata determinata e pubblicata la struttura dell’ossidoreduttasi da H. pylori 26695, cioè HP0377. Poiché la loro sequenza amminoacidica presenta un elevato grado di identità (96%), le indagini sono state considerate non più innovative.
Nel Capitolo VII sono descritti il clonaggio, l’espressione, la purificazione e le prove di cristallizzazione per quanto riguarda due “proteine ipotetiche” secrete, cioè HPG27_1030 e HPG27_1117. Recentemente numerose proteine secrete sono state identificate tramite analisi proteomica del secretoma di H. pylori; queste rappresentano interessanti soggetti di indagini strutturali e funzionali, poiché potrebbero mediare importanti interazioni tra ospite e patogeno e, quindi, concorrere come potenziali target per lo sviluppo di antibiotici e vaccini. HPG27_1030 è stata clonata con successo come proteina ricombinante con un 6-His-tag, espressa in cellule di E. coli e purificata tramite due passaggi cromatografici. È stato possibile ottenere una quantità molti rilevante di proteina solubile, questa ha esibito un’elevata instabilità in soluzione e una chiara tendenza all’aggregazione, portando perciò a una limitata concentrazione finale di campione purificato per le prove di cristallizzazione. HPG27_1117 è stata clonata, espressa e purificata come riportato sopra. I limiti più rilevanti che sono stati incontrati sono una bassa resa di espressione e la tendenza alla degradazione del campione. Nonostante ciò, la proteina purificata è stata concentrata per le prove di cristallizzazione e sono stati ottenuti cristalli utilizzando il metodo di diffusione di vapore; ma questi hanno diffranto ad una risoluzione troppo limitata e non è stato possibile ottenere cristalli di qualità adatta per le misure di diffrazione a raggi X. Per superare il problema comune dell’instabilità e della degradazione di queste proteine secrete, cambiamenti nella composizione dei tamponi di purificazione potrebbe migliorare la stabilità in soluzioni e così la resa finale di prodotto purificato per le prove di cristallizzazione.
In conclusione, grazie all’individuazione di alcune nuove peculiarità di questo patogeno è stato possibile accrescere la conoscenza in merito a H. pylori e i suoi meccanismi peculiari volti alla sopravvivenza e alla virulenza. Questi primi risultati costituiscono la base per nuove investigazioni, al fine di apprendere nel modo più completo possibile i meccanismi patofisiologici di questo peculiare microorganismo e di sviluppare nuovi trattamenti per l’eradicazione.

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Tipo di EPrint:Tesi di dottorato
Relatore:Zanotti, Giuseppe
Dottorato (corsi e scuole):Ciclo 28 > Scuole 28 > BIOSCIENZE E BIOTECNOLOGIE > BIOTECNOLOGIE
Data di deposito della tesi:31 Gennaio 2016
Anno di Pubblicazione:30 Gennaio 2016
Parole chiave (italiano / inglese):Helicobacter pylori, protein crystallography, enzyme, structural characterization, carbonic anhydrases, thiol:disulfide oxidoreductase, flagellar hook-length control protein, HPG27_1030, HPG27_1117
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/10 Biochimica
Struttura di riferimento:Centri > Centro Interdipartimentale di servizi A. Vallisneri
Dipartimenti > Dipartimento di Biologia
Codice ID:9515
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Abdollahi, Hamid and Omid Tadjrobehkar. 2012. “The Role of Different Sugars, Amino Acids and Few Other Substances in Chemotaxis Directed Motility of Helicobacter Pylori.” Iranian Journal of Basic Medical Sciences 15(3):787–94. Cerca con Google

Adams, Paul D. et al. 2010. “PHENIX: A Comprehensive Python-Based System for Macromolecular Structure Solution.” Acta crystallographica. Section D, Biological crystallography 66(Pt 2):213–21. Cerca con Google

Agarwal, K. and S. Agarwal. 2008. “Helicobacter Pylori Vaccine : From Past to Future.” Mayo Clinic Proceedings 83(2):169–75. Cerca con Google

Aggarwal, Mayank et al. 2014. “Structural Insight into Activity Enhancement and Inhibition of H64A Carbonic Anhydrase II by Imidazoles.” IUCrJ 1(1):129–35. Cerca con Google

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Ahmed, Niyaz, Shivendra Tenguria, and Nishant Nandanwar. 2009. “Helicobacter Pylori--a Seasoned Pathogen by Any Other Name.” Gut pathogens 1:24. Cerca con Google

Akada, Junko K., Mutsunori Shirai, Hiroaki Takeuchi, Masataka Tsuda, and Teruko Nakazawa. 2000. “Identification of the Urease Operon in Helicobacter Pylori and Its Control by mRNA Decay in Response to pH.” Molecular Microbiology 36:1071–84. Cerca con Google

Akhiani, Ali a et al. 2002. “Protection against Helicobacter Pylori Infection Following Immunization Is IL-12-Dependent and Mediated by Th1 Cells.” Journal of immunology (Baltimore, Md. : 1950) 169(12):6977–84. Cerca con Google

Algood, H. M. S. and T. L. Cover. 2006. “Helicobacter Pylori Persistence: An Overview of Interactions between H. Pylori and Host Immune Defenses.” Clinical Microbiology Reviews 19(4):597–613. Cerca con Google

Alm, R. A. et al. 1998. “Genomic-Sequence Comparison of Two Unrelated Isolates of the Human Gastric Pathogen Helicobacter Pylori.” Nature 395(2):863–69. Cerca con Google

Alm, R. A. and T. J. Trust. 1999. “Analysis of the Genetic Diversity of Helicobacter Pylori: The Tale of Two Genomes.” Journal of molecular medicine (Berlin, Germany) 77(12):834–46. Cerca con Google

Amieva, Manuel R. et al. 2003. “Disruption of the Epithelial Apical-Junctional Complex by Helicobacter Pylori CagA.” Science (New York, N.Y.) 300(5624):1430–34. Cerca con Google

Amieva, Manuel R. and Emad M. El-Omar. 2008. “Host-Bacterial Interactions in Helicobacter Pylori Infection.” Gastroenterology 134(1):306–23. Cerca con Google

Andersen, Leif Percival. 2007. “Colonization and Infection by Helicobacter Pylori in Humans.” Helicobacter 12 Suppl 2:12–15. Cerca con Google

Andersen, Leif Percival and Lone Rasmussen. 2009. “Helicobacter Pylori - Coccoid Forms and Biofilm Formation.” FEMS Immunology and Medical Microbiology 56(2):112–15. Cerca con Google

Aras, R. A. 2002. “Helicobacter Pylori Interstrain Restriction-Modification Diversity Prevents Genome Subversion by Chromosomal DNA from Competing Strains.” Nucleic Acids Research 30(24):5391–97. Cerca con Google

Aras, Rahul a, Josephine Kang, Ariane I. Tschumi, Yasuaki Harasaki, and Martin J. Blaser. 2003. “Extensive Repetitive DNA Facilitates Prokaryotic Genome Plasticity.” Proceedings of the National Academy of Sciences of the United States of America 100(23):13579–84. Cerca con Google

Aspholm, Marina et al. 2006. “SabA Is the H. Pylori Hemagglutinin and Is Polymorphic in Binding to Sialylated Glycans.” PLoS pathogens 2(10):e110. Cerca con Google

Aspinall, G. O. and M. A. Monteiro. 1996. “Lipopolysaccharides of Helicobacter Pylori Strains P466 and MO19: Structures of the O Antigen and Core Oligosaccharide Regions.” Biochemistry 35(7):2498–2504. Cerca con Google

Atherton, J. C., R. M. Jr Peek, K. T. Tham, T. L. Cover, and M. J. Blaser. 1997. “Clinical and Pathological Importance of Heterogeneity in vacA, the Vacuolating Cytotoxin Gene of Helicobacter Pylori.” Gastroenterology 112(1):92–99. Cerca con Google

Atherton, J. C., K. T. Tham, R. M. Peek, T. L. Cover, and M. J. Blaser. 1996. “Density of Helicobacter Pylori Infection in Vivo as Assessed by Quantitative Culture and Histology.” The Journal of infectious diseases 174(3):552–56. Cerca con Google

Atherton, JC et al. 1995. “Mosaicism in Vacuolating Cytotoxin Alleles of Helicobacter Pylori. Association of Specific VacA Types with Cytotoxin Production and Peptic Ulcerataion.” Journal of Biological Chemistry 270(30):17771–77. Cerca con Google

Ayala, Guadalupe, Wendy Itzel Escobedo-Hinojosa, Carlos Felipe de la Cruz-Herrera, and Irma Romero. 2014. “Exploring Alternative Treatments for Helicobacter Pylori Infection.” World journal of gastroenterology : WJG 20(6):1450–69. Cerca con Google

Backert, Steffen and Matthias Selbach. 2008. “Role of Type IV Secretion in Helicobacter Pylori Pathogenesis.” Cellular Microbiology 10(8):1573–81. Cerca con Google

Baidya, Amit K., Saurabh Bhattacharya, and Rukhsana Chowdhury. 2015. “Role of the Flagellar Hook-Length Control Protein FliK and σ28 in cagA Expression in Gastric Cell–Adhered Helicobacter Pylori.” Journal of Infectious Diseases 211:1779–89. Cerca con Google

Baltrus, David a. et al. 2009. “The Complete Genome Sequence of Helicobacter Pylori Strain G27.” Journal of Bacteriology 91(1):447–48. Cerca con Google

Bamford, K. B. et al. 1998. “Lymphocytes in the Human Gastric Mucosa during Helicobacter Pylori Have a T Helper Cell 1 Phenotype.” Gastroenterology 114(3):482–92. Cerca con Google

Bardhan, Pradip K. 1997. “Epidemiological Features of Helicobacter Pylori Infection in Developing Countries.” Clinical Infectious Diseases 973–78. Cerca con Google

Barker, P. D. and S. J. Ferguson. 1999. “Still a Puzzle: Why Is Haem Covalently Attached in c-Type Cytochromes?” Structure (London, England : 1993) 7(12):R281–90. Cerca con Google

Basso, Daniela et al. 2008. “Clinical Relevance of Helicobacter Pylori cagA and vacA Gene Polymorphisms.” Gastroenterology 135(1):91–99. Cerca con Google

Becker, Holger M., Michael Klier, and Joachim W. Deitmer. 2014. Carbonic Anhydrase: Mechanism, Regulation, Links to Disease, and Industrial Applications. Cerca con Google

Bellack, N. R., M. W. Koehoorn, Y. C. MacNab, and M. G. Morshed. 2006. “A Conceptual Model of Water’s Role as a Reservoir in Helicobacter Pylori Transmission: A Review of the Evidence.” Epidemiology and infection 134(3):439–49. Cerca con Google

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Blaser, Martin J., Yu Chen, and Joan Reibman. 2008. “Does Helicobacter Pylori Protect against Asthma and Allergy?” Gut 57(5):561–67. Cerca con Google

Bocian-Ostrzycka, Katarzyna M., Magdalena J. Grzeszczuk, Lukasz Dziewit, and Elżbieta K. Jagusztyn-Krynicka. 2015. “Diversity of the Epsilonproteobacteria Dsb (disulfide Bond) Systems.” Frontiers in microbiology 6(June):570. Cerca con Google

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Bonnard, Geraldine, Vincent Corvest, Etienne H. Meyer, and Patrice P. Hamel. 2010. “Redox Processes Controlling the Biogenesis of c-Type Cytochromes.” Antioxidants & redox signaling 13(9):1385–1401. Cerca con Google

Boone, Christopher D., Melissa Pinard, Rob McKenna, and David Silverman. 2014. “Catalytic Mechanism of Alpha-Class Carbonic Anhydrases: CO2 Hydration and Proton Transfer.” Sub-cellular biochemistry 75:31–52. Cerca con Google

Boren, T., P. Falk, K. A. Roth, G. Larson, and S. Normark. 1993. “Attachment of Helicobacter Pylori to Human Gastric Epithelium Mediated by Blood Group Antigens.” Science (New York, N.Y.) 262(5141):1892–95. Cerca con Google

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Brown, L. M. 2000. “Helicobacter Pylori: Epidemiology and Routes of Transmission.” Epidemiologic Reviews 22(2):283–97. Cerca con Google

Bukanov, N. O. and D. E. Berg. 1994. “Ordered Cosmid Library and High-Resolution Physical-Genetic Map of Helicobacter Pylori Strain NCTC11638.” Molecular microbiology 11(3):509–23. Cerca con Google

Bumann, D. et al. 2002. “Proteome Analysis of Secreted Proteins of the Gastric Pathogen Helicobacter Pylori.” Infect Immun 70(7):3396–3403. Cerca con Google

Bury-Moné, Stéphanie et al. 2003. “Presence of Active Aliphatic Amidases in Helicobacter Species Able to Colonize the Stomach.” Infection and immunity 71(10):5613–22. Cerca con Google

Bury-Moné, Stéphanie et al. 2004. “Responsiveness to Acidity via Metal Ion Regulators Mediates Virulence in the Gastric Pathogen Helicobacter Pylori.” Molecular microbiology 53(2):623–38. Cerca con Google

Bury-Moné, Stéphanie et al. 2008. “Roles of Alpha and Beta Carbonic Anhydrases of Helicobacter Pylori in the Urease-Dependent Response to Acidity and in Colonization of the Murine Gastric Mucosa.” Infection and immunity 76(2):497–509. Cerca con Google

Busler, V. J. et al. 2006. “Protein-Protein Interactions among Helicobacter Pylori Cag Proteins.” Journal of Bacteriology 188(13):4787–4800. Cerca con Google

Byrd, J. C., C. K. Yunker, Q. S. Xu, L. R. Sternberg, and R. S. Bresalier. 2000. “Inhibition of Gastric Mucin Synthesis by Helicobacter Pylori.” Gastroenterology 118(6):1072–79. Cerca con Google

Capasso, Clemente and Claudiu T. Supuran. 2015. “An Overview of the Alpha-, Beta- and Gamma-Carbonic Anhydrases from Bacteria: Can Bacterial Carbonic Anhydrases Shed New Light on Evolution of Bacteria?” Journal of enzyme inhibition and medicinal chemistry 30(2):325–32. Cerca con Google

Carlsohn, Elisabet, Johanna Nyström, Ingrid Bölin, Carol L. Nilsson, and Ann-Mari Svennerholm. 2006. “HpaA Is Essential for Helicobacter Pylori Colonization in Mice.” Infection and immunity 74(2):920–26. Cerca con Google

Carraway, K. L. and S. R. Hull. 1991. “Cell Surface Mucin-Type Glycoproteins and Mucin-like Domains.” Glycobiology 1(2):131–38. Cerca con Google

Cascales, E. and P. J. Christie. 2003. “The Versatile Bacterial Type IV Secretion Systems.” Nature reviews. Microbiology 18(9):1199–1216. Cerca con Google

Ceci, Pierpaolo, Laura Mangiarotti, Claudio Rivetti, and Emilia Chiancone. 2007. “The Neutrophil-Activating Dps Protein of Helicobacter Pylori, HP-NAP, Adopts a Mechanism Different from Escherichia Coli Dps to Bind and Condense DNA.” Nucleic acids research 35(7):2247–56. Cerca con Google

Cendron, Laura and Giuseppe Zanotti. 2011. “Structural and Functional Aspects of Unique Type IV Secretory Components in the Helicobacter Pylori Cag-Pathogenicity Island.” FEBS Journal 278(8):1223–31. Cerca con Google

Censini, S. et al. 1996. “Cag , a Pathogenicity Island of Helicobacter Pylori , Encodes Type I-Specific and Disease-Associated Virulence Factors.” Proceedings of the National Academy of Sciences of the United States of America 93(December):14648–53. Cerca con Google

Cerda, Oscar A. et al. 2011. “tlpA Gene Expression Is Required for Arginine and Bicarbonate Chemotaxis in Helicobacter Pylori.” Biological research 44(3):277–82. Cerca con Google

Ceruso, Mariangela et al. 2015. “Inhibition Studies of Bacterial, Fungal and Protozoan β-Class Carbonic Anhydrases with Schiff Bases Incorporating Sulfonamide Moieties.” Bioorganic & Medicinal Chemistry 23(15):4181–87. Cerca con Google

Chevance, Fabienne F. V and Kelly T. Hughes. 2008. “Coordinating Assembly of a Bacterial Macromolecular Machine.” Nat Rev Micro 6(6):455–65. Cerca con Google

Chirica, L. C., B. Elleby, and S. Lindskog. 2001. “Cloning, Expression and Some Properties of Alpha-Carbonic Anhydrase from Helicobacter Pylori.” Biochimica et biophysica acta 1544(1-2):55–63. Cerca con Google

Chiurillo, Miguel Angel et al. 2013. “Genotyping of Helicobacter Pylori Virulence-Associated Genes Shows High Diversity of Strains Infecting Patients in Western Venezuela.” International Journal of Infectious Diseases 17(9):750–56. Cerca con Google

Choli-Papadopoulou, Theodora. 2011. “Helicobacter Pylori Neutrophil Activating Protein as Target for New Drugs against H. Pylori Inflammation.” World Journal of Gastroenterology 17(21):2585. Cerca con Google

Cid, Trinidad Parra, Miryam Calvino Fernández, Selma Benito Martínez, and Nicola L. Jones. 2013. “Pathogenesis of Helicobacter Pylori Infection.” Helicobacter 18:12–17. Cerca con Google

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Contreras, Monica, Jean Michel Thiberge, M. a. Mandrand-Berthelot, and Agnès Labigne. 2003. “Characterization of the Roles of NikR, a Nickel-Responsive Pleiotropic Autoregulator of Helicobacter Pylori.” Molecular Microbiology 49(4):947–63. Cerca con Google

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