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Plasmodium falciparum Infection Induces Expression of a Mosquito Salivary Protein (Agaphelin) That Targets Neutrophil Function and Inhibits Thrombosis without Impairing Hemostasis
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نویسنده
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waisberg m. ,molina-cruz a. ,mizurini d.m. ,gera n. ,sousa b.c. ,ma d. ,leal a.c. ,gomes t. ,kotsyfakis m. ,ribeiro j.m.c. ,lukszo j. ,reiter k. ,porcella s.f. ,oliveira c.j. ,monteiro r.q. ,barillas-mury c. ,pierce s.k. ,francischetti i.m.b.
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منبع
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plos pathogens - 2014 - دوره : 10 - شماره : 9
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چکیده
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Invasion of mosquito salivary glands (sgs) by plasmodium falciparum sporozoites is an essential step in the malaria life cycle. how infection modulates gene expression,and affects hematophagy remains unclear.using affimetrix chip microarray,we found that at least 43 genes are differentially expressed in the glands of plasmodium falciparum-infected anopheles gambiae mosquitoes. among the upregulated genes,one codes for agaphelin,a 58-amino acid protein containing a single kazal domain with a leu in the p1 position. agaphelin displays high homology to orthologs present in aedes sp and culex sp salivary glands,indicating an evolutionarily expanded family. kinetics and surface plasmon resonance experiments determined that chemically synthesized agaphelin behaves as a slow and tight inhibitor of neutrophil elastase (kd∼10 nm),but does not affect other enzymes,nor promotes vasodilation,or exhibit antimicrobial activity. taxiscan chamber assay revealed that agaphelin inhibits neutrophil chemotaxis toward fmlp,affecting several parameter associated with cell migration. in addition,agaphelin reduces paw edema formation and accumulation of tissue myeloperoxidase triggered by injection of carrageenan in mice. agaphelin also blocks elastase/cathepsin-mediated platelet aggregation,abrogates elastase-mediated cleavage of tissue factor pathway inhibitor,and attenuates neutrophil-induced coagulation. notably,agaphelin inhibits neutrophil extracellular traps (nets) formation and prevents fecl3-induced arterial thrombosis,without impairing hemostasis.blockade of neutrophil elastase emerges as a novel antihemostatic mechanism in hematophagy; it also supports the notion that neutrophils and the innate immune response are targets for antithrombotic therapy. in addition,agaphelin is the first antihemostatic whose expression is induced by plasmodium sp infection. these results suggest that an important interplay takes place in parasite-vector-host interactions. © 2014 public library of science. all rights reserved.
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آدرس
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laboratory of immunogenetics,national institute of allergy and infectious diseases,national institutes of health,bethesda,md,united states,department of pathology,university of virginia,charlottesville,va, United States, laboratory of malaria and vector research,national institute of allergy and infectious diseases,national institutes of health,bethesda,md, United States, instituto de bioquimica médica,federal university of rio de janeiro,rio de janeiro, Brazil, laboratory of immunogenetics,national institute of allergy and infectious diseases,national institutes of health,bethesda,md, United States, instituto de ciências biológicas e naturais,universidade federal do triângulo mineiro,uberaba, Brazil, laboratory of malaria and vector research,national institute of allergy and infectious diseases,national institutes of health,bethesda,md, United States, instituto de bioquimica médica,federal university of rio de janeiro,rio de janeiro, Brazil, instituto de bioquimica médica,federal university of rio de janeiro,rio de janeiro, Brazil, institute of parasitology,academy of sciences of the czech republic,české budjovice, Czech Republic, laboratory of malaria and vector research,national institute of allergy and infectious diseases,national institutes of health,bethesda,md, United States, research technology branch,national institute of allergy and infectious diseases,national institutes of health,rockville,md, United States, research technology branch,national institute of allergy and infectious diseases,national institutes of health,rockville,md, United States, genomics unit,research technology section,rocky mountain labs,national institute of allergy and infectious diseases,national institutes of health,hamilton,mt, United States, instituto de ciências biológicas e naturais,universidade federal do triângulo mineiro,uberaba, Brazil, instituto de bioquimica médica,federal university of rio de janeiro,rio de janeiro, Brazil, laboratory of malaria and vector research,national institute of allergy and infectious diseases,national institutes of health,bethesda,md, United States, laboratory of immunogenetics,national institute of allergy and infectious diseases,national institutes of health,bethesda,md, United States, laboratory of malaria and vector research,national institute of allergy and infectious diseases,national institutes of health,bethesda,md, United States
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Authors
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