Please use this identifier to cite or link to this item: https://www.arca.fiocruz.br/handle/icict/8398
Title: Interplay between parasite cysteine proteases and the host kinin system modulates microvascular leakage and macrophage infection by promastigotes of the Leishmania donovani complex.
Authors: Svensjö, Nils Erik
Batista, Paulo Ricardo
Brodskyn, Claudia Ida
Silva, Robson Amaro Augusto da
Lima, Ana Paula Cabral de Araujo
Pereira, Verônica Schmitz
Bou Habib, Elvira Maria Saraiva Chequer
Pesquero, João Bosco
Mori, Marcelo Alves da Silva
Müller-Esterl, Werner
Scharfstein, Julio
Affilliation: Fundação Oswaldo Cruz. Centro de Pesquisa Gonçalo Moniz. Salvador, BA, Brasil
Universidade Federal do Rio de Janeiro. Instituto de Biofísica Carlos Chagas Filho. Rio de Janeiro, RJ, Brasil
Fundação Oswaldo Cruz. Centro de Pesquisa Gonçalo Moniz. Salvador, BA, Brasil
Fundação Oswaldo Cruz. Centro de Pesquisa Gonçalo Moniz. Salvador, BA, Brasil
Fundação Oswaldo Cruz. Centro de Pesquisa Gonçalo Moniz. Salvador, BA, Brasil
Fundação Oswaldo Cruz. Centro de Pesquisa Gonçalo Moniz. Salvador, BA, Brasil
Universidade Federal do Rio de Janeiro. Instituto de Microbiologia Paulo de Góes. Rio de Janeiro, RJ, Brasil
Universidade Federal do Estado de São Paulo. UNIFESP. Escola Paulista de Medicina. Departamento de Biofísica. São Paulo, SP, Brasil
Universidade Federal do Estado de São Paulo. UNIFESP. Escola Paulista de Medicina. Departamento de Biofísica. São Paulo, SP, Brasil
University of Frankfurt Medical School. Institute for Biochemistry II. Frankfurt, Germany
Fundação Oswaldo Cruz. Centro de Pesquisa Gonçalo Moniz. Salvador, BA, Brasil
Abstract: Kinins, 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.
Keywords: Leishmaniasis
Innate immunity
Inflammation
Macrophages
Endothelium
Kinins
Angiotensin-converting enzyme
Cysteine proteases
DeCS: Permeabilidade Capilar/fisiologia
Cisteína Endopeptidases/metabolismo
Cininas/metabolismo
Leishmania donovani/enzimologia
Leishmania infantum/enzimologia
Macrófagos/metabolismo
Animais
Cricetinae
Deleção de Genes
Masculino
Camundongos
Camundongos Endogâmicos BALB C
Peptidil Dipeptidase A/metabolismo
Receptores da Bradicinina/genética
Receptores da Bradicinina/metabolismo
Fatores de Tempo
Issue Date: 2006
Publisher: Elsevier SAS
Citation: SVENSJO, 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.
DOI: 10.1016/j.micinf.2005.06.016
ISSN: 1286-4579
Copyright: open access
Appears in Collections:BA - IGM - Artigos de Periódicos

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