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

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

Autor Svensjo, E. Google Scholar
Batista, P. R. Google Scholar
Brodskyn, C. I. Google Scholar
Silva, R. Google Scholar
Lima, APCA Google Scholar
Schmitz, V Google Scholar
Saraiva, E. Google Scholar
Pesquero, J. B. Google Scholar
Mori, MAS Google Scholar
Muller-Esterl, W. Google Scholar
Scharfstein, J. Google Scholar
Instituição Universidade Federal do Rio de Janeiro (UFRJ)
Ctr Pesquisa Goncalo Moniz
Universidade Federal de São Paulo (UNIFESP)
Univ Frankfurt
Resumo 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 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.
Palavra-chave Leishmaniasis
innate immunity
inflammation
macrophages
endothelium
kinins
angiotensin-converting enzyme
cysteine proteases
Idioma Inglês
Data de publicação 2006-01-01
Publicado em Microbes and Infection. Amsterdam: Elsevier B.V., v. 8, n. 1, p. 206-220, 2006.
ISSN 1286-4579 (Sherpa/Romeo, fator de impacto)
Publicador Elsevier B.V.
Extensão 206-220
Fonte http://dx.doi.org/10.1016/j.micinf.2005.06.016
Direito de acesso Acesso restrito
Tipo Artigo
Web of Science WOS:000235441700024
Endereço permanente http://repositorio.unifesp.br/handle/11600/28649

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