A protein secreted in vivo by Echinococcus granulosus inhibits elastase activity and neutrophil chemotaxis

Shepherd, James; Aitken, Alastair; McManus, Donald P.

doi:10.1016/0166-6851(91)90223-s

Cited by 154 publications

(98 citation statements)

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“…Thus, it is not surprising to find proteins in tick saliva that are able to inhibit these two processes. Among key players in these, leukocyte elastase is possibly detrimental to different steps of the ticks' blood meal through (i) activation of plasminogen into plasmin, (ii) hydrolysis of fibrin clots, (iii) activation of a pro-inflammatory response (54,55), and (iv) digestion of the extracellular matrix and destruction of tick's gut tissues.…”

Section: Discussionmentioning

confidence: 99%

Anti-hemostatic Effects of a Serpin from the Saliva of the Tick Ixodes ricinus

Prévôt

Adam

Boudjeltia

et al. 2006

Journal of Biological Chemistry

108

130

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Serpins (serine protease inhibitors) are a large family of structurally related proteins found in a wide variety of organisms, including hematophagous arthropods. Protein analyses revealed that Iris, previously described as an immunomodulator secreted in the tick saliva, is related to the leukocyte elastase inhibitor and possesses serpin motifs, including the reactive center loop (RCL), which is involved in the interaction between serpins and serine proteases. Only serine proteases were inhibited by purified recombinant Iris (rIris), whereas mutants L339A and A332P were found devoid of any protease inhibitory activity. The highest K a was observed with human leukocyteelastase, suggesting that elastase-like proteases are the natural targets of Iris. In addition, mutation M340R completely changed both Iris substrate specificity and affinity. This likely identified Met-340 as amino acid P1 in the RCL. The effects of rIris and its mutants were also tested on primary hemostasis, blood clotting, and fibrinolysis. rIris increased platelet adhesion, the contact phase-activated pathway of coagulation, and fibrinolysis times in a dose-dependent manner, whereas rIris mutant L339A affected only platelet adhesion. Taken together, these results indicate that Iris disrupts coagulation and fibrinolysis via the anti-proteolytic RCL domain. One or more other domains could be responsible for primary hemostasis inhibition. To our knowledge, this is the first ectoparasite serpin that interferes with both hemostasis and the immune response.Ticks are blood-sucking arthropods that infest a large variety of vertebrate hosts (mammals, birds, reptiles, and amphibians) in many parts of the world (1). To complete their blood meal, blood-sucking arthropods express a wide range of anti-hemostatic molecules in their saliva, including vasodilators, inhibitors of the platelet aggregation, and anti-coagulants (2). Tick saliva and salivary gland extracts are also known to modulate the host's defense mechanisms (3-6). Both anti-hemostatic and immunosuppressive compounds were identified, isolated, and characterized from soft and hard ticks. These compounds include histamine-binding proteins, tissue factor pathway inhibitor-like proteins, anti-thrombin-like proteins, and anticomplement factors (7-16).These last years, several laboratories reported the construction and screening of cDNA libraries from tick salivary glands. Thus, Das et al. (17) found 14 Ixodes scapularis immunodominant antigens, whereas Leboulle et al. (18) identified 27 mRNA, the expression of which is specifically induced or up-regulated during the Ixodes ricinus blood meal. Finally, Ribeiro and coworkers explored the sialome of the tick I. scapularis (19,20) and uncovered a large variety of putative bioactive agents. These studies all identified some serine protease inhibitors, containing serpin, kunitz, kazal, or ␣-macroglobulin motifs (21).To date, ϳ500 serpins have been identified in a large variety of species, including animals, viruses, and plants. On average, serpins are 35...

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Section: Discussionmentioning

confidence: 99%

Anti-hemostatic Effects of a Serpin from the Saliva of the Tick Ixodes ricinus

Prévôt

Adam

Boudjeltia

et al. 2006

Journal of Biological Chemistry

108

130

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“…About 10% of the hydatid fluid protein fraction is composed by a polymeric thermo-stable lipoprotein (Musiani et al, 1978), the antigen B (AgB), whose role in the immune response evasion is suggested by several lines of evidence. First, the antigen inhibits neutrophil chemotaxis and elastases in vitro (Shepherd et al, 1991); second, it elicits a non-protective Th2 immune response (Riganú et al, 2001); and, finally, it induces immune cell apopoptosis in patients with hydatid disease (Riganú et al, 2002). The native antigen, built by subunits of 8 kDa, is highly immunoreactive.…”

Section: Introductionmentioning

confidence: 99%

Contingent, non-neutral evolution in a multicellular parasite: natural selection and gene conversion in the Echinococcus granulosus antigen B gene family

Haag

Alves-Junior

Zaha

et al. 2004

Gene

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“…The antigen is present in large amounts in the metacestode cyst fluid, and its biological functions suggest that it may play a relevant role in the host/parasite interaction. AgB has been reported as a protease inhibitor that impairs the recruitment of polymorphonuclear cells and skews the Th1/Th2 cytokine ratio toward an immunopathology-associated Th2 polarization (4,5). In human infections, AgB is highly immunogenic, which has prompted its use as a diagnostic reagent.…”

mentioning

confidence: 99%

Identification of Critical Residues of an Immunodominant Region of Echinococcus granulosus Antigen B

González‐Sapienza

Cachau

2003

Journal of Biological Chemistry

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Immune evasion strategies often shape the immunogenicity of parasite components. We recently found that the N-terminal extension of the major subunit of Echinococcus granulosus antigen B (AgB), the causative agent of hydatid disease, concentrates the immunoreactive B cell epitopes of the native molecule. The nature of this immunodominance was analyzed using four monoclonal antibodies (mAbs) defining overlapping epitopes in this region of the AgB molecule. The minimal epitope requirements of these mAbs were determined using phage display peptide libraries. The consensus sequences isolated with the mAbs, and alanine replacement analysis with synthetic peptides mapped the relevant molecular contacts within a short stretch corresponding to residues 17-24 of the AgB major subunit. Substitution of two critical residues within this stretch produced a dramatic loss of antigenicity, as determined by using patient sera. The circular dichroism spectra of the antigen, together with the distribution of the contact residues, suggest that this region adopts an amphipathic ␣-helix structure that clusters the contact residues on its polar side. To provide further insight in the interpretation of the structure activity relationships for this immunoreactive region of E. granulosus AgB, we developed a model for the N-terminal extension of the AgB major subunit, which helps to rationalize our data.Antigen B (AgB), 1 the major antigens of Echinococcus granulosus, the causative agent of cystic hydatid disease, is a 120-kDa protein composed of multimers of homologous but different 8-kDa subunits (AgB8/1, AgB8/2, and AgB8/3) (1-3). The antigen is present in large amounts in the metacestode cyst fluid, and its biological functions suggest that it may play a relevant role in the host/parasite interaction. AgB has been reported as a protease inhibitor that impairs the recruitment of polymorphonuclear cells and skews the Th1/Th2 cytokine ratio toward an immunopathology-associated Th2 polarization (4, 5). In human infections, AgB is highly immunogenic, which has prompted its use as a diagnostic reagent. In fact, AgB possesses the highest diagnostic value among the major E. granulosus antigens (6), and we have found that p176, a 38-mer synthetic peptide representing the N-terminal extension of AgB8/1, exhibits higher diagnostic sensitivity and specificity than native AgB (7). This is a singular finding considering that, in general, synthetic peptides are poor mimics of the parent epitope and, accordingly, exhibit low diagnostic sensitivities. There are several reasons for this. First, the full group of contact atoms of a given antibody/antigen interface are seldom derived from a short linear stretch of the antigen (8); second, the structural conformation of peptides is not restricted in solution, and there is therefore an unfavorable entropic component to the binding (9). In addition, a single peptide mimics a partial region of the parent protein and, consequently, only a fraction of the polyclonal antibody response against the native antigen...

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A protein secreted in vivo by Echinococcus granulosus inhibits elastase activity and neutrophil chemotaxis

Cited by 154 publications

References 28 publications

Anti-hemostatic Effects of a Serpin from the Saliva of the Tick Ixodes ricinus

Anti-hemostatic Effects of a Serpin from the Saliva of the Tick Ixodes ricinus

Contingent, non-neutral evolution in a multicellular parasite: natural selection and gene conversion in the Echinococcus granulosus antigen B gene family

Identification of Critical Residues of an Immunodominant Region of Echinococcus granulosus Antigen B

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