P. falciparum Isolate-Specific Distinct Patterns of Induced Apoptosis in Pulmonary and Brain Endothelial Cells

Abstract

The factors implicated in the transition from uncomplicated to severe clinical malaria such as pulmonary oedema and cerebral malaria remain unclear. It is known that alterations in vascular integrity due to endothelial cell (EC) activation and death occur during severe malaria. In this study, we assessed the ability of different P. falciparum clinical isolates to induce apoptosis in ECs derived from human lung and brain. We observed that induction of EC apoptosis was sensitive to the environmental pH and required direct contact between the parasite and the cell, though it was not correlated to the ability of the parasite to cytoadhere. Moreover, the extent of induced apoptosis in the two EC types varied with the isolate. Analysis of parasite genes transcript led us to propose that the activation of different pathways, such as Plasmodium apoptosis–linked pathogenicity factors (PALPF), PALPF-2, PALPF-5 and PF11_0521, could be implied in EC death. These observations provide an experimental framework to decipher the molecular mechanism implicated in the genesis of severe malaria.

Interplay of Plasmodium falciparum and thrombin in brain endothelial barrier disruption

“…Of interest, there was also a relatively low cell death in primary HBMEC compared to previous work on immortalized brain endothelial cells showing much higher cell death 61,62 and increased death following TNFα activation 64 . There are several possible explanations for these discrepancies, including that the susceptibility to apoptosis has been found to differ between primary pulmonary endothelial cells and immortalized brain endothelial cells 61,63 . Moreover, the cell death inducing phenotype differs between parasite isolates 61,63,70,71 and is influenced by the buffering capacity of culture media 63 .…”

Dysregulation of pulmonary endothelial protein C receptor and thrombomodulin in severe falciparum malaria-associated ARDS relevant to hemozoin

“…Thus, it is suggested that in addition to the pro-inflammatory effects induced by hemozoin, alveolar epithelial cell damage was directly caused by s-hemozoin due to its pro-oxidative properties [40] via an apoptotic pathway. Recently, an in vitro study of P. falciparum, isolates demonstrated that apoptosis in pulmonary endothelial cells is sensitive to oxidative environments and requires direct contact between the parasite and host cells, otherwise PRBCs are sequestered alone [43]. Therefore, the oxidative properties of hemozoin may destroy the pulmonary epithelium and lead to acute lung injury.…”

Dynamic interactions ofPlasmodiumspp. with vascular endothelium

“…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. Moreover, the extent of induced apoptosis in the 2 endothelial cell types was inhibited by pan-caspase or caspase-8 inhibitors and varied with the isolate.…”