Article
Interplay between parasite cysteine proteases and the host kinin system modulates microvascular leakage and macrophage infection by promastigotes of the Leishmania donovani complex.
Registro en:
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.
1286-4579
10.1016/j.micinf.2005.06.016
Autor
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
Resumen
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.
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