Rho Kinase Inhibition in Severe Malaria: Thwarting Parasite‐Induced Collateral Damage to Endothelia

Abstract

Acute clinical manifestations of falciparum malaria, such as multiorgan failure and cerebral malaria, occur unpredictably and lead to coma and death within hours if left untreated. Despite the emergency administration of effective antimalarial drugs, 15%-20% of patients die. Other therapeutic approaches are therefore urgently needed. There is increasing evidence that endothelial changes play a key role in the pathogenesis of severe malaria. We therefore used coculture models to study interactions between infected erythrocytes and endothelium. We found that adhesion of Plasmodium falciparum to endothelial cells in vitro activated the Rho kinase signaling pathway, which is strongly involved in various vascular diseases. When added concomitantly with parasites, the Rho kinase inhibitor fasudil (HA-1077), a drug already in clinical use, decreased both NF-kappaB activation and endothelial cell apoptosis. Fasudil also helped to restore endothelial barrier integrity after P. falciparum adhesion. Rho kinase inhibition thus appears to be a promising adjunctive therapeutic approach to the management of severe human malaria.

Dynamic interactions ofPlasmodiumspp. with vascular endothelium

“…The increase in endothelial permeability and apoptosis induced by IRBC has also been linked to Rho A activation and was partially inhibited by the ROCK inhibitor fasudil but the parasite agonists, host receptors and downstream effectors, such as actin stress fiber formation, were not determined. 134 In other studies, cell death is either not observed 47,49,135 or could not be attributed to the activation of caspases. Treatment of primary dermal and lung endothelial cells with P. falciparum histones has been shown to induce cell death which was insensitive to a pan-caspase inhibitor.…”

“…Endothelial cell apoptosis has been implicated as a mechanism of increased endothelial permeability, 46,[132][133][134] and different clinical isolates of P. falciparum appeared to induce apoptosis to varying degrees in primary endothelial cells derived from human lung and brain. 133 The induction of endothelial apoptosis was sensitive to the environmental pH and required direct contact between the parasite and the endothelial cell, although adhesion to specific receptors was not essential.…”

Physiopathology of Malaria-Associated Acute Respiratory Distress Syndrome

“…Most severe cases are related to P. falciparum (Table 1) associated with high mortality, while severe disease could be caused by all species [19][20][21][22]. In humans, they are associated to many complications mainly influenced by individual factors such as age, exposure and their immune status, occurring mainly in children, pregnant women and those primary infected due to immunological factors, and also by the species and virulence of Plasmodium.…”

Signal transduction in Plasmodium-Red Blood Cells interactions and in cytoadherence

“…Fasudil also helped to restore endothelial barrier integrity after IE adhesion. Rho kinase inhibition thus appears to be a promising adjunctive therapeutic agent for severe malaria (Taoufiq et al 2008). Fasudil was also tested in patient isolates at schizont stage in contact and non-contact experiments with HLEC.…”