Is there a role for bradykinin in cerebral malaria pathogenesis?

Abstract

Malaria is a parasitic disease of global health significance and a leading cause of death in children living in endemic regions. Although various Plasmodium species are responsible for the disease, Plasmodium falciparum infection accounts for most severe cases of the disease in humans. The mechanisms of cerebral malaria pathogenesis have been studied extensively in humans and animal malaria models; however, it is far from being fully understood. Recent discoveries indicate a potential role of bradykinin and the kallikrein kinin system in the pathogenesis of cerebral malaria. The aim of this review is to highlight how bradykinin is formed in cerebral malaria and how it may impact cerebral blood-brain barrier function. Areas of interest in this context include Plasmodium parasite enzymes that directly generate bradykinin from plasma protein precursors, cytoadhesion of P. falciparum infected red blood cells to brain endothelial cells, and endothelial cell blood-brain barrier disruption.

Keywords: bradykinin; bradykinin B2 and B1 receptors; cerebral malaria; factor XII; high molecule weight kininogen; prekallikrein.

Figure 1

Physiologic bradykinin forming pathways in the intravascular compartment. PK, prekallikrein; PKa, plasma kallikrein; PRCP, prolylcarboxypeptidase; FXII, factor XII; FXIIa, activated factor XII; HK, high molecular weight kininogen; cHK, cleaved HK or bradykinin-free HK; BK, bradykinin; B2R, bradykinin B2; B1R, bradykinin B1 receptor. There are two physiologic mechanisms for BK formation in the intravascular compartment. The first is on the left of the figure. It shows that on a negatively activated surface, e.g., PolyP, factor XII autoactivates into an enzyme FXIIa. FXIIa then activates zymogen PK to plasma PKa). A second mechanism to form PKa is on the right. PK bound to endothelial cells by HK is proteolyzed by a membrane expressed PRCP. PKa formed by any mechanism cleaves the HK it is bound to, liberating BK and leaving a residual bradykinin-free HK or cHK. Formed BK binds to its endothelial cell constitutive receptor, the B2R to stimulate endothelial cell activation. In inflammatory states, a second receptor, termed the B1R also is expressed to mediate BK’s effect on endothelial cell biology. Figure made with Biorender.

Figure 2

Bradykinin (BK) formation in cerebral malaria. HK, high molecular weight kininogen; PK, plasma prekallikrein; PKa, plasma kallikrein; FXII, factor XII; FXIIa, activated FXII; cHK, cleaved (bradykinin free) high molecular weight kininogen. There are 3 ways iRBCs may lead to BK formation. 1) Falcipain-2 itself released from Plasmodium falciparum cleaves HK to liberate BK; 2) The ruptured membranes or microparticles/exosomes from P. falciparum infected RBCs or parasites themselves support FXII autoactivation leading to PKa formation that liberates BK from HK; 3) Occluding P. falciparum infected red blood cells upregulate an endothelial cell PK activator (Protease) that leads to more PKa activation with cleavage of HK liberating BK to produce edema in the vessel wall. Figure made with Biorender.