Interplay between parasite cysteine proteases and the host kinin system modulates microvascular leakage and macrophage infection by promastigotes of the Leishmania donovani complex

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dc.contributor.authorSvensjo, E.
dc.contributor.authorBatista, P. R.
dc.contributor.authorBrodskyn, C. I.
dc.contributor.authorSilva, R.
dc.contributor.authorLima, APCA
dc.contributor.authorSchmitz, V
dc.contributor.authorSaraiva, E.
dc.contributor.authorPesquero, J. B.
dc.contributor.authorMori, MAS
dc.contributor.authorMuller-Esterl, W.
dc.contributor.authorScharfstein, J.
dc.contributor.institutionUniversidade Federal do Rio de Janeiro (UFRJ)
dc.contributor.institutionCtr Pesquisa Goncalo Moniz
dc.contributor.institutionUniversidade Federal de São Paulo (UNIFESP)
dc.contributor.institutionUniv Frankfurt
dc.date.accessioned2016-01-24T12:38:17Z
dc.date.available2016-01-24T12:38:17Z
dc.date.issued2006-01-01
dc.description.abstractKinins, the vasoactive peptides proteolytically liberated from kininogens, were recently recognized as signals alerting the innate immune system. Here we demonstrate that Leishmania donovani and Leishmania chagasi, two etiological agents of visceral leishmaniasis (VL), activate the kinin system. Intravital microscopy in the hamster cheek pouch showed that topically applied promastigotes induced macromolecular leakage (FITC-dextran) through postcapillary venules. Peaking at 15 min, the parasite-induced leakage was drastically enhanced by captopril (Cap), an inhibitor of angiotensin-converting enzyme (ACE), a kinin-degrading metallopeptidase. the enhanced microvascular responses were cancelled by HOE-140, an antagonist of the B, bradykinin receptor (13,R), or by pre-treatment of promastigotes with the irreversible cysteine proteinase inhibitor N-methylpiperazine-urea-Phe-homoPhe-vinylsulfone-benzene (N-Pip-hF-VSPh). in agreement with the above-mentioned data, the promastigotes vigorously induced edema in the paw of Cap-treated J129 mice, but not Cap-B2R-/(-) mice. Analysis of parasite-induced breakdown of high molecular weight kininogens (HK), combined with active site-affinity-labeling with biotin-N-Pip-hF-VSPh, identified 35-40 kDa proteins as kinin-releasing cysteine peptidases. We then checked if macrophage infectivity was influenced by interplay between these kinin-releasing parasite proteases, kininogens, and kinin-degrading peptidases (i.e. ACE). Our studies revealed that full-fledged B2R engagement resulted in vigorous increase of L. chagasi uptake by resident macrophages. Evidence that inflammatory macrophages treated with HOE-140 became highly susceptible to amastigote outgrowth, assessed 72 h after initial macrophage interaction, further suggests that the kinin/B2R activation pathway may critically modulate inflammation and innate immunity in visceral leishmaniasis. (c) 2005 Elsevier SAS. All rights reserved.en
dc.description.affiliationUniv Fed Rio de Janeiro, Inst Biofis Carlos Chagas Filho, BR-21949900 Rio de Janeiro, Brazil
dc.description.affiliationCtr Pesquisa Goncalo Moniz, LIP, BR-40295001 Salvador, BA, Brazil
dc.description.affiliationUniv Fed Rio de Janeiro, Inst Microbiol Paulo Goes, BR-21949900 Rio de Janeiro, Brazil
dc.description.affiliationUniversidade Federal de São Paulo, Dept Biofis, São Paulo, Brazil
dc.description.affiliationUniv Frankfurt, Sch Med, Inst Biochem 2, D-6000 Frankfurt, Germany
dc.description.affiliationUnifespUniversidade Federal de São Paulo, Dept Biofis, São Paulo, Brazil
dc.description.sourceWeb of Science
dc.format.extent206-220
dc.identifierhttp://dx.doi.org/10.1016/j.micinf.2005.06.016
dc.identifier.citationMicrobes and Infection. Amsterdam: Elsevier B.V., v. 8, n. 1, p. 206-220, 2006.
dc.identifier.doi10.1016/j.micinf.2005.06.016
dc.identifier.issn1286-4579
dc.identifier.urihttp://repositorio.unifesp.br/handle/11600/28649
dc.identifier.wosWOS:000235441700024
dc.language.isoeng
dc.publisherElsevier B.V.
dc.relation.ispartofMicrobes and Infection
dc.rightsinfo:eu-repo/semantics/restrictedAccess
dc.rights.licensehttp://www.elsevier.com/about/open-access/open-access-policies/article-posting-policy
dc.subjectLeishmaniasisen
dc.subjectinnate immunityen
dc.subjectinflammationen
dc.subjectmacrophagesen
dc.subjectendotheliumen
dc.subjectkininsen
dc.subjectangiotensin-converting enzymeen
dc.subjectcysteine proteasesen
dc.titleInterplay between parasite cysteine proteases and the host kinin system modulates microvascular leakage and macrophage infection by promastigotes of the Leishmania donovani complexen
dc.typeinfo:eu-repo/semantics/article
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