Vascular dysfunction as a target for adjuvant therapy in cerebral malaria

Abstract

Cerebral malaria (CM) is a life-threatening complication of Plasmodium falciparum malaria that continues to be a major global health problem. Brain vascular dysfunction is a main factor underlying the pathogenesis of CM and can be a target for the development of adjuvant therapies for the disease. Vascular occlusion by parasitised red blood cells and vasoconstriction/vascular dysfunction results in impaired cerebral blood flow, ischaemia, hypoxia, acidosis and death. In this review, we discuss the mechanisms of vascular dysfunction in CM and the roles of low nitric oxide bioavailability, high levels of endothelin-1 and dysfunction of the angiopoietin-Tie2 axis. We also discuss the usefulness and relevance of the murine experimental model of CM by Plasmodium berghei ANKA to identify mechanisms of disease and to screen potential therapeutic interventions.

Endothelin-1 Treatment Induces an Experimental Cerebral Malaria–Like Syndrome in C57BL/6 Mice Infected with Plasmodium berghei NK65

“…In addition, it is well known that activation of endothelial cells releases ET-1, 67,68 and multiple factors, such as hypoxia, IL-1, tumor necrosis factor-a, interferon-g, certain Plasmodium falciparum erythrocyte membrane protein 1 subtypes, leukocyte activation, free heme release, and low nitric oxide bioavailability, have been implicated in the endothelial cell activation during human and ECM. 2 As noted previously, the lipid moiety of hemozoin binds ET-1. 66 This may further contribute to increased concentrations of ET-1 at sites of pRBC sequestration, as lysed RBCs have been shown to release ET-1 in response to certain stimuli.…”

“…1 Brain vascular dysfunction is an important factor underlying CM pathophysiology, resulting in impaired cerebral blood flow, hemorrhage, hypoxia, blood-brain barrier (BBB) leakage, and, ultimately, coma and death. 2,3 Vascular occlusion of the brain microvasculature by parasitized red blood cells (pRBCs), vasoconstriction, and BBB leakage are the three main components of CM vasculopathy 4e6 ; however, the mediators and mechanisms that trigger these processes are not completely understood.…”

Multiple Organ Dysfunction During Severe Malaria: The Role of the Inflammatory Response

“…Several soluble proteins have been described such as inflammatory markers of endothelial activation during severe malaria. The angiopoietin (Ang)-Tie2 axis is a critical regulator of endothelial quiescence, activation and dysfunction in infectious and oncologic diseases, atherosclerosis, and pulmonary hypertension [53,54]. Ang-1 signals through its cognate receptor Tie-2 (a tyrosine kinase with immunoglobulin and endothelial growth factor homology domains), which is expressed on endothelial cells [53].…”

“…In addition, Ang-2 (partial/weak agonist of Tie-2) is released by endothelial cells and acts as an Ang-1 antagonist [55]. During cerebral malaria (CM), Ang-1 exerts anti-inflammatory effects by decreasing adhesion molecule expression and maintaining the integrity of the BBB by reinforcing VE-cadherin tight junctions [53,54]. In contrast, Ang-2 is stored in Weibel-Palade bodies (WPB) within endothelial cells and is involved in the response to inflammatory stimuli.…”

Evidencing the Role of Erythrocytic Apoptosis in Malarial Anemia

“…In view of the pathophysiological significance of erythrocytic apoptosis, our group has attempted to study this erythrocytic process in malaria, a vector-borne infection caused by protozoa of the genus Plasmodium that infect RBCs and induce strong hematologic and vascular disturbances (Anstey et al, 2009; Grau and Craig, 2012; Carvalho et al, 2014). Our studies have shown that induction of apoptosis is not limited to parasitized RBCs (pRBCs) but also occurs in non-parasitized RBCs (nRBCs), pointing to an involvement of both pRBC and nRBC in the pathogenesis of malaria through deflagration of suicide processes (Totino et al, 2009, 2011, 2013, 2014).…”