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Arcidiacono, Diletta (2008) VCC, citolisina di Vibrio cholerae,promuove secrezione di cloruro dalle cellule intestinali e produzione di citochine TH2 nei mastociti. [Tesi di dottorato]

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Abstract (inglese)

Cholera has long been considered a classic paradigm of a non-inflammatory toxigenic diarrhoea until Vibrio cholerae infection was found to induce a TH2-type of immune profile and the recruitment of inflammatory cells in the intestinal mucosa (Mathan MM, 1995; Qadri F, 2000).
Recent reports indicate increased levels of inflammatory mediators in patients infected by Vibrio cholerae that occur in parallel with recruitment of innate immune cells, including mast cells and neutrophils, in the crypt and villus lamina propria (Qadri F, 2004).
Enteropathogenic Vibrio cholerae can elaborate different exotoxins: cholera toxin (CT), zonula occludens toxin and a membrane damaging toxin, referred to as haemolysin or Vibrio cholerae cytolysin (VCC).
VCC is a water soluble toxin secreted as a 79 kDa inactive pro-hemolysin (Alm RA, 1988; Yamamoto K, 1990), which is proteolytically cleaved within its N-terminal part (Nagamune K, 1997) to generate the mature toxin of 63 kDa.
In cholesterol-and ceramides-rich membranes (Zitzer A, 1999) VCC forms heptameric channels, with a moderate anion preference, responsible for vacuolization and eventual lysis of several cell types in culture (Coelho A, 2000; Figueroa-Arredondo P, 2001; Moschioni M, 2002; Pantano S, 2006).
VCC is believed to contribute to the development of cholera diarrhoea (Ichinose Y, 1987).
On the basis of its channel property and considering that the majority of the diarrhogenic toxins affect chloride secretion in the intestine (Laohachai KN, 2003), we have investigated whether VCC was able to promote an efflux of chloride from intestinal epithelial cells.
We find that the hemolysin induces an efflux of chloride from intestinal epithelial cells; consequently it might either cause diarrhoea per se, in the non producing cholera toxin strains, or contribute to cause diarrhoea when the toxin is present.

Considering the recent demonstration of the abundance of mast cells in cholera patients and on the basis that no other bacterial factors have been identified as immune modulator so far, we decided to address the possibility that VCC could be such a factor, by evaluating its ability in activating mucosal mast cells.
Here we suggest that VCC could contribute to the T helper 2 (TH2) response seen in the natural infection; acting through TLR2, VCC enhances mast cells secretion of IL-4, IL-6 and TNF-alpha by 330-, 290- and 550-fold respectively.
Moreover, VCC-induced cytokine production is dependent on increased cytosolic Ca2+ and on the presence of the Src family kinases Lyn and Fyn, known to be required for FcepsilonRI-dependent activation of mast cells.
These findings strongly suggest that VCC has a pro-inflammatory activity promoting a TH2-type immune profile.

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Tipo di EPrint:Tesi di dottorato
Relatore:de Bernard, Marina
Dottorato (corsi e scuole):Ciclo 20 > Scuole per il 20simo ciclo > BIOSCIENZE > BIOLOGIA CELLULARE
Data di deposito della tesi:29 Gennaio 2008
Anno di Pubblicazione:29 Gennaio 2008
Parole chiave (italiano / inglese):VCC, Vibrio cholerae, intestino, mastociti, Th2
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/19 Microbiologia generale
Struttura di riferimento:Dipartimenti > Dipartimento di Scienze Biomediche Sperimentali
Codice ID:703
Depositato il:11 Nov 2008
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