A genetically detoxified derivative of heat-labile Escherichia coli enterotoxin induces neutralizing antibodies against the A subunit.

Pizza, Mariagrazia; Fontana, Maria Rita; Giuliani, Marzia M.; Domenighini, M; Magagnoli, Claudia; Giannelli, V; Nucci, Daniele; Hol, W.G.J.; Manetti, Roberto; Rappuoli, Rino

doi:10.1084/jem.180.6.2147

Cited by 103 publications

(91 citation statements)

References 41 publications

(46 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…An alternative approach to circumvent this problem is the use of genetically detoxified heat labile enterotoxins of E. coli LTK63 or non-toxic mutant cholera toxin CT S61F. 125,134,135 The challenge currently faced by several laboratories is to discover whether or not the promising results obtained in the animal model can be reproduced in humans.…”

Section: Vaccination Development For Clinical Use and Future Of The Hmentioning

confidence: 99%

Helicobacter pylori: recent advances in the study of its pathogenicity and prevention

Aguilar¹,

Ayala²,

Fierros-Zarate³

2001

Salud pública Méx

View full text Add to dashboard Cite

Helicobacter pylori has acquired great importance during the last two decades, after being recognized as an important pathogen that infects a great portion of the human population. This microorganism is recognized as the main causal agent of chronic gastritis and duodenal ulcers, and it is associated with the subsequent development of gastric carcinoma. The pathogenic mechanisms of H. pylori and their relation to gastric ailments have not been clearly defined. However, at present it is well established that urease, vacuolating cytotoxin VacA, and the pathogenicity island (cag PAI) gene products, are the main factors of virulence of this organism. Thus, individuals infected with strains that express these virulence factors probably develop a severe local inflammation that may induce the development of peptic ulcer and gastric cancer. The way the infection spreads throughout the world suggests the possibility that there are multiple pathways of transmission. Due to the importance that H. pylori has acquired as a human pathogen, laboratories worldwide are attempting to develop a vaccine that confers long-term immunological protection against infection by this microorganism. Hence, the objective of this review is to present the most relevant findings of the biology of H. Pylori and its interaction with the human host. The full version of this paper is available too at: http:// www.insp.mx/salud/index.html ResumenHelicobacter pylori ha adquirido gran importancia durante las últimas dos décadas, al ser reconocido como un importante patógeno que infecta una gran porción de la población humana. Este microrganismo es reconocido como el principal agente que causa la gastritis crónica y la úlcera duodenal, además de que se ha asociado con el subsecuente desarrollo del carcinoma gástrico. Los mecanismos patogé-nicos de H. pylori y su relación con los padecimientos gás-tricos no se han definido en forma clara. Sin embargo, actualmente está bien establecido que la ureasa, la citotoxina vacuolizante VacA y los productos de los genes de la isla de patogenicidad (cag PAI) son los principales factores de virulencia de este organismo. Así, los individuos infectados con cepas que expresan dichos factores de virulencia, probablemente manifiesten una marcada inflamación local que podría inducir el desarrollo de úlcera péptica y cáncer gástri-co. La manera como la infección se propaga a nivel mundial sugiere la posibilidad de múltiples vías de transmisión. A consecuencia de la importancia que H. pylori ha adquirido como patógeno humano, los laboratorios del mundo se esfuerzan para desarrollar una vacuna que confiera protección inmunológica de larga duración contra la infección por este microorganismo. El objetivo de esta revisión es presentar los hallazgos más relevantes sobre la biología de H. pylori y su interacción con su huésped humano. El texto completo de este artículo también está disponible en:

show abstract

Section: Vaccination Development For Clinical Use and Future Of The Hmentioning

confidence: 99%

Helicobacter pylori: recent advances in the study of its pathogenicity and prevention

Aguilar¹,

Ayala²,

Fierros-Zarate³

2001

Salud pública Méx

View full text Add to dashboard Cite

show abstract

“…One LT variant, named LT4, showed the same amino acid composition as the previously reported pLT, and in vivo and in vitro results indicated that this LT type has reduced toxicity with regard to the most ubiquitous LT1 and LT2 types (22). Of note, pLT has been used for definition of the LT tertiary structure and as a template for the generation of nontoxic or attenuated LT derivatives used as vaccine adjuvants (4,5,(7)(8)(9). In fact, during the last three decades, pLT and hLT were considered similar both with regard to their toxic effects and immunomodulatory activities in murine hosts, but no direct comparison of the two toxins has been reported so far.…”

Section: Enterotoxigenic Escherichia Coli (Etec)mentioning

confidence: 78%

“…To avoid the mucosal toxicity exhibited by the native toxin, different LT mutants with reduced toxic effect but partially preserved adjuvanticity were tested in the murine model (13,14). Among the several LT mutants generated under laboratory conditions, LTK63 and LTR72, with no or drastically reduced enzymatic activity, and LTR192G, lacking the trypsin cleavage site, have been intensively investigated as potential mucosal adjuvants in the mouse model (8,9,15).…”

Section: Enterotoxigenic Escherichia Coli (Etec)mentioning

confidence: 99%

“…The A1 domain carries the catalytic site, which is delimited by the ADP-binding crevice that binds to NAD and subsequently transfers the ADP-ribose moiety to the target protein (6). Several site-specific mutants contributed to the understanding of LT structural/functional relationships, such as LTK63, in which the serine at position 63 of the A1 domain active site was replaced with lysine (7,8). This LT mutant shows a complete knock-out of enzymatic activity but preserves the structural features of the parental toxin.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Functional Diversity of Heat-labile Toxins (LT) Produced by Enterotoxigenic Escherichia coli

Rodrigues

Mathias-Santos

Sbrogio-Almeida

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

Heat-labile toxins (LTs) have ADP-ribosylation activity and induce the secretory diarrhea caused by enterotoxigenic Escherichia coli (ETEC) strains in different mammalian hosts. LTs also act as adjuvants following delivery via mucosal, parenteral, or transcutaneous routes. Previously we have shown that LT produced by human-derived ETEC strains encompass a group of 16 polymorphic variants, including the reference toxin (LT1 or hLT) produced by the H10407 strain and one variant that is found mainly among bacterial strains isolated from pigs (LT4 or pLT). Herein, we show that LT4 (with six polymorphic sites in the A (K4R, K213E, and N238D) and B (S4T, A46E, and E102K) subunits) displays differential in vitro toxicity and in vivo adjuvant activities compared with LT1. One in vitro generated LT mutant (LTK4R), in which the lysine at position 4 of the A subunit was replaced by arginine, showed most of the LT4 features with an ϳ10-fold reduction of the cytotonic effects, ADP-ribosylation activity, and accumulation of intracellular cAMP in Y1 cells. Molecular dynamic studies of the A subunit showed that the K4R replacement reduces the N-terminal region flexibility and decreases the catalytic site crevice. Noticeably, LT4 showed a stronger Th1-biased adjuvant activity with regard to LT1, particularly concerning activation of cytotoxic CD8 ؉ T lymphocytes when delivered via the intranasal route. Our results further emphasize the relevance of LT polymorphism among human-derived ETEC strains that may impact both the pathogenicity of the bacterial strain and the use of these toxins as potential vaccine adjuvants.Enterotoxigenic Escherichia coli (ETEC) 3 is a major etiological agent of diarrhea, afflicting both young children and travelers in developing countries, with high morbidity and mortality rates. ETEC also causes diarrheal disease in livestock, especially in piglets, representing an economically relevant problem (1, 2). ETEC pathogenicity is directly linked to the production of fimbrial or afimbrial colonization factor antigens and heat-stable and/or heat-labile toxin (LT) (1). LT belongs to the family of AB 5 toxins consisting of an enzymatically active A subunit, proteolytically processed into the larger and enzymatic active A1 domain and the shorter A2 domain and five B subunits that mediate binding to glycolipid and glycoprotein receptors of host cells. The B monomer (11.5 kDa) pentamer interacts with the A subunit (28 kDa) via noncovalent binding to the A2 domain. The A1 domain is responsible for ADP-ribosylation of stimulatory G protein, leading to uncontrolled elevation of the intracellular cAMP concentration. Consequently, ion permeases open, and chloride anions and water molecules are released, a hallmark of the watery diarrhea caused by ETEC infection (3).The structure of LT is closely related to the biological functions of the toxin. The A subunit has an overall globular structure and is linked to the compact cylinder-like structure formed by the five B monomers, which expose the residues involved with bind...

show abstract

“…While CT has been the standard for mucosal adjuvant activity, the toxicity of the A subunit has discouraged clinical use [174]. LT also has toxicity associated with its A subunit, but mutants with signifi cantly lower toxicity have been generated [175,176]. The mutants LTK63 and LTR72 have been shown to have potent activity in the generation of mucosal antibody in preclinical models against a variety of antigens when administered by oral, nasal [177], or transdermal routes [178] and appear ready for clinical testing [177].…”

Section: Historical Progressionmentioning

confidence: 99%

Development of Vaccine Adjuvants: A Historical Perspective

Ott

Nest

2006

Vaccine Adjuvants and Delivery Systems

View full text Add to dashboard Cite

A genetically detoxified derivative of heat-labile Escherichia coli enterotoxin induces neutralizing antibodies against the A subunit.

Cited by 103 publications

References 41 publications

Helicobacter pylori: recent advances in the study of its pathogenicity and prevention

Helicobacter pylori: recent advances in the study of its pathogenicity and prevention

Functional Diversity of Heat-labile Toxins (LT) Produced by Enterotoxigenic Escherichia coli

Development of Vaccine Adjuvants: A Historical Perspective

Contact Info

Product

Resources

About