Abstract
BackgroundThe malaria burden remains a major public health concern, especially in sub-Saharan Africa. The complex biology of Plasmodium, the apicomplexan parasite responsible for this disease, challenges efforts to develop new strategies to control the disease. Proteolysis is a fundamental process in the metabolism of malaria parasites, but roles for proteases in generating vasoactive peptides have not previously been explored.ResultsIn the present work, it was demonstrated by mass spectrometry analysis that Plasmodium parasites (Plasmodium chabaudi and Plasmodium falciparum) internalize and process plasma kininogen, thereby releasing vasoactive kinins (Lys-BK, BK and des-Arg9-BK) that may mediate haemodynamic alterations during acute malaria. In addition, it was demonstrated that the P. falciparum cysteine proteases falcipain-2 and falcipain-3 generated kinins after incubation with human kininogen, suggesting that these enzymes have an important role in this process. The biologic activity of peptides released by Plasmodium parasites was observed by measuring ileum contraction and activation of kinin receptors (B1 and B2) in HUVEC cells; the peptides elicited an increase in intracellular calcium, measured by Fluo-3 AM fluorescence. This effect was suppressed by the specific receptor antagonists Des-Arg9[Leu8]-BK and HOE-140.ConclusionsIn previously undescribed means of modulating host physiology, it was demonstrated that malaria parasites can generate active kinins by proteolysis of plasma kininogen.
Highlights
The malaria burden remains a major public health concern, especially in sub-Saharan Africa
Recent studies demonstrated that the Plasmodium falciparum cysteine proteases falcipain-2 and falcipain-3 act with similar specificity in haemoglobin degradation, not via an ordered hydrolytic pathway, but through rapid hydrolysis at multiple sites [7]
During the Trypanosoma cruzi infection, immature dendritic cells (DC) sense the presence of the parasite in the peripheral and lymphoid tissues by B2R stimulation mediated by bradykinin, which is generated by action of its major cysteine protease, cruzipain
Summary
The malaria burden remains a major public health concern, especially in sub-Saharan Africa. Kinins are biologically active peptides released from a multifunctional plasma protein, kininogen (HK) They can induce vasodilatation, stimulate the production of nitric oxide, activate endothelial cells, enhance microvascular permeability and modulate the metabolism of different tissues [15,16,17,18,19]. During the Trypanosoma cruzi infection, immature dendritic cells (DC) sense the presence of the parasite in the peripheral and lymphoid tissues by B2R stimulation mediated by bradykinin, which is generated by action of its major cysteine protease, cruzipain. These activated DC trigger a cascade of immune cells activation, culminating in the generation of immunoprotection by IFN-γ-producing T cells [24]. These kinins promote B2R pathway activation that, in conjunction with TLR2 activation by the bacterial LPS, modulates effector T cells commitment in the pathology [26]
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