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

dc.creatorSvensjö, Nils Erik
dc.creatorBatista, Paulo Ricardo
dc.creatorBrodskyn, Claudia Ida
dc.creatorSilva, Robson Amaro Augusto da
dc.creatorLima, Ana Paula Cabral de Araujo
dc.creatorPereira, Verônica Schmitz
dc.creatorBou Habib, Elvira Maria Saraiva Chequer
dc.creatorPesquero, João Bosco
dc.creatorMori, Marcelo Alves da Silva
dc.creatorMüller-Esterl, Werner
dc.creatorScharfstein, Julio
dc.date2014-09-18T16:18:30Z
dc.date2014-09-18T16:18:30Z
dc.date2006
dc.date.accessioned2023-09-26T22:09:24Z
dc.date.available2023-09-26T22:09:24Z
dc.identifierSVENSJO, E. et al. Interplay between parasite cysteine proteases and the host kinin system modulates microvascular leakage and macrophage infection by promastigotes of the Leishmania donovani complex. Microbes Infection, v.8, n. 1, p. 206-220, 2006.
dc.identifier1286-4579
dc.identifierhttps://www.arca.fiocruz.br/handle/icict/8398
dc.identifier10.1016/j.micinf.2005.06.016
dc.identifier.urihttps://repositorioslatinoamericanos.uchile.cl/handle/2250/8875517
dc.descriptionKinins, 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 B2 bradykinin receptor (B2R), 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.
dc.formatapplication/pdf
dc.languageeng
dc.publisherElsevier SAS
dc.rightsopen access
dc.subjectLeishmaniasis
dc.subjectInnate immunity
dc.subjectInflammation
dc.subjectMacrophages
dc.subjectEndothelium
dc.subjectKinins
dc.subjectAngiotensin-converting enzyme
dc.subjectCysteine proteases
dc.subjectPermeabilidade Capilar/fisiologia
dc.subjectCisteína Endopeptidases/metabolismo
dc.subjectCininas/metabolismo
dc.subjectLeishmania donovani/enzimologia
dc.subjectLeishmania infantum/enzimologia
dc.subjectMacrófagos/metabolismo
dc.subjectAnimais
dc.subjectCricetinae
dc.subjectDeleção de Genes
dc.subjectMasculino
dc.subjectCamundongos
dc.subjectCamundongos Endogâmicos BALB C
dc.subjectPeptidil Dipeptidase A/metabolismo
dc.subjectReceptores da Bradicinina/genética
dc.subjectReceptores da Bradicinina/metabolismo
dc.subjectFatores de Tempo
dc.titleInterplay between parasite cysteine proteases and the host kinin system modulates microvascular leakage and macrophage infection by promastigotes of the Leishmania donovani complex.
dc.typeArticle


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