Potential role for excretory–secretory forms of glutathione-S-transferase (GST) in <i>Fasciola hepatica</i>

Cervi, Laura; Rossi, Gabriela R.; Masih, Diana T.

doi:10.1017/s003118209900517x

Cited by 59 publications

(43 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Based on this enzymatic activity, many parasitic helminth GSTs play an important role in detoxifying the secondary products of lipid peroxidation produced via immune-initiated free-radical attack on host or parasite membranes (3,7,26). In this sense, helminth GSTs are immunomodulatory.…”

Section: Discussionmentioning

confidence: 99%

Biochemical Characterization and Vaccine Potential of a Heme-Binding Glutathione Transferase from the Adult Hookworm Ancylostoma caninum

Zhan¹,

Liu²,

Perally

et al. 2005

Infect Immun

View full text Add to dashboard Cite

We report the cloning and expression of Ac-GST-1, a novel glutathione S-transferase from the adult hookworm Ancylostoma caninum, and its possible role in parasite blood feeding and as a vaccine target. The predicted Ac-GST-1 open reading frame contains 207 amino acids (mass, 24 kDa) and exhibited up to 65% amino acid identity with other nematode GSTs. mRNA encoding Ac-GST-1 was detected in adults, eggs, and larval stages, but the protein was detected only in adult hookworm somatic extracts and excretory/secretory products. Using antiserum to the recombinant protein, Ac-GST-1 was immunolocalized to the parasite hypodermis and muscle tissue and weakly to the intestine. Recombinant Ac-GST-1 was enzymatically active, as determined by conjugation of glutathione to a model substrate, and exhibited a novel high-affinity binding site for hematin. The possible role of Ac-GST-1 in parasite heme detoxification during hemoglobin digestion or heme uptake prompted interest in evaluating it as a potential vaccine antigen. Vaccination of dogs with Ac-GST-1 resulted in a 39.4% reduction in the mean worm burden and 32.3% reduction in egg counts compared to control dogs following larval challenge, although the reductions were not statistically significant. However, hamsters vaccinated with Ac-GST-1 exhibited statistically significant worm reduction (53.7%) following challenge with heterologous Necator americanus larvae. These studies suggest that Ac-GST-1 is a possible drug and vaccine target for hookworm infection.Hookworm infection is a major cause of disease burden for animals and humans. An estimated 740 million cases of human hookworm infection occur worldwide (12). Most of the pathology attributed to hookworm infection results from intestinal blood loss caused by the adult stages of the parasite (21, 32). The adult hookworm is specially adapted to ingest red blood cells and feed on the intracellular contents and has evolved to produce a battery of molecules for this purpose (22,42). For instance, the parasite uses its buccal capsule to attach to the intestinal mucosa and submucosa, where it mechanically ruptures capillaries and arterioles. From unique cephalic glands, the adult hookworm releases anticoagulants and anti-platelet-aggregating agents into the attachment site (10, 34). The parasite subsequently ruptures red blood cells through the action of a unique hemolysin (13) and then degrades the released hemoglobin through a carefully orchestrated cascade of hemoglobinases (43). This sequence of events is central to the pathogenesis of hookworm disease, which results almost entirely from hookworm-induced blood loss leading to iron deficiency anemia (35).The trichostrongyle Hemonchus contortus is a major cause of anemia and weight loss in small ruminants. Like hookworms, H. contortus produces numerous mechanistically distinct proteases that are thought to digest hemoglobin (27). Recently, adult H. contortus was shown to produce a novel glutathione S-transferase (Hc-GST-1), which has a high-affinity binding site for hematin ...

show abstract

Section: Discussionmentioning

confidence: 99%

Biochemical Characterization and Vaccine Potential of a Heme-Binding Glutathione Transferase from the Adult Hookworm Ancylostoma caninum

Zhan¹,

Liu²,

Perally

et al. 2005

Infect Immun

View full text Add to dashboard Cite

show abstract

“…It is likely that GSTs can elicit in vivo complex cellular interactions that may modulate host immune response. As an example, the dimeric form of GST present in the excretory-secretory products of Fasciola hepatica modulates T cell proliferation in vitro and NO production by normal peritoneal macrophages (36).…”

Section: Discussionmentioning

confidence: 99%

TheTrypanosoma cruziTc52-Released Protein Induces Human Dendritic Cell Maturation, Signals Via Toll-Like Receptor 2, and Confers Protection Against Lethal Infection

Ouaissi

Guilvard

Delneste

et al. 2002

The Journal of Immunology

126

View full text Add to dashboard Cite

The intracellular protozoan parasite Trypanosoma cruzi is the etiological agent of Chagas disease. We have recently identified a T. cruzi-released protein related to thiol-disulfide oxidoreductase family, called Tc52, which is crucial for parasite survival and virulence. In vitro, Tc52 in combination with IFN-γ activates human macrophages. In vivo, active immunization with Tc52 relieves the immunosuppression associated to acute infection and elicits a specific immune response. As dendritic cells (DC) have a central role in the initiation of immune responses, we investigated whether Tc52 may modulate DC activity. We show that Tc52 induces human DC maturation. Tc52-treated immature DC acquire CD83 and CD86 expression, produce inflammatory chemokines (IL-8, monocyte chemoattractant protein-1, and macrophage-inflammatory protein-1α), and present potent costimulatory properties. Tc52 binds to DC by a mechanism with the characteristics of a saturable receptor system and signals via Toll-like receptor 2. While Tc52-mediated signaling involves its reduced glutathione-binding site, another portion of the molecule is involved in Tc52 binding to DC. Finally, we report that immunization with Tc52 protects mice in vivo against lethal infection with T. cruzi. Together these data evidence complex molecular interactions between the T. cruzi-derived molecule, Tc52, and DC, and suggest that Tc52 and related class of proteins might represent a new type of pathogen-associated molecular patterns. Moreover, the immune protection data suggest that Tc52 is among candidate molecules that may be used to design an optimal multicomponent vaccine to control T. cruzi infection.

show abstract

“…Parasite GSTs are believed to be involved in the detoxification of endogenously produced toxic compounds or host immune-initiated reactive oxygen species (ROS), as well as the transportation or metabolism of a variety of essential materials for parasites (57). Due to their critical roles in parasite-host interactions, GSTs have been targeted for pharmaceutical and vaccine purposes and have demonstrated protective effects against some parasites (11,17,34). For instance, a GST from schistosomes is currently a lead vaccine candidate for human schistosomiasis caused by Schistosoma haematobium (7) and Schistosoma mansoni (4) and is undergoing phase II and phase III clinical trials (15,41).…”

mentioning

confidence: 99%

Molecular Cloning, Biochemical Characterization, and Partial Protective Immunity of the Heme-Binding GlutathioneS-Transferases from the Human HookwormNecator americanus

et al. 2010

View full text Add to dashboard Cite

Hookworm glutathione S-transferases (GSTs) are critical for parasite blood feeding and survival and represent potential targets for vaccination. Three cDNAs, each encoding a full-length GST protein from the human hookworm Necator americanus (and designated Na-GST-1, Na-GST-2, and Na-GST-3, respectively) were isolated from cDNA based on their sequence similarity to Ac-GST-1, a GST from the dog hookworm Ancylostoma caninum. The open reading frames of the three N. americanus GSTs each contain 206 amino acids with 51% to 69% sequence identity between each other and Ac-GST-1. Sequence alignment with GSTs from other organisms shows that the three Na-GSTs belong to a nematode-specific nu-class GST family. All three Na-GSTs, when expressed in Pichia pastoris, exhibited low lipid peroxidase and glutathione-conjugating enzymatic activities but high heme-binding capacities, and they may be involved in the detoxification and/or transport of heme. In two separate vaccine trials, recombinant Na-GST-1 formulated with Alhydrogel elicited 32 and 39% reductions in adult hookworm burdens (P < 0.05) following N. americanus larval challenge relative to the results for a group immunized with Alhydrogel alone. In contrast, no protection was observed in vaccine trials with Na-GST-2 or Na-GST-3. On the basis of these and other preclinical data, Na-GST-1 is under possible consideration for further vaccine development.

show abstract

Potential role for excretory–secretory forms of glutathione-S-transferase (GST) in Fasciola hepatica

Cited by 59 publications

References 22 publications

Biochemical Characterization and Vaccine Potential of a Heme-Binding Glutathione Transferase from the Adult Hookworm Ancylostoma caninum

Biochemical Characterization and Vaccine Potential of a Heme-Binding Glutathione Transferase from the Adult Hookworm Ancylostoma caninum

TheTrypanosoma cruziTc52-Released Protein Induces Human Dendritic Cell Maturation, Signals Via Toll-Like Receptor 2, and Confers Protection Against Lethal Infection

Molecular Cloning, Biochemical Characterization, and Partial Protective Immunity of the Heme-Binding GlutathioneS-Transferases from the Human HookwormNecator americanus

Contact Info

Product

Resources

About