Plasmodium falciparum Histones Induce Endothelial Proinflammatory Response and Barrier Dysfunction

Abstract

Plasmodium falciparum is a protozoan parasite of human erythrocytes that causes the most severe form of malaria. Severe P. falciparum infection is associated with endothelial activation and permeability, which are important determinants of the outcome of the infection. How endothelial cells become activated is not fully understood, particularly with regard to the effects of parasite subcomponents. We demonstrated that P. falciparum histones extracted from merozoites (HeH) directly stimulated the production of IL-8 and other inflammatory mediators by primary human dermal microvascular endothelial cells through a signaling pathway that involves Src family kinases and p38 MAPK. The stimulatory effect of HeH and recombinant P. falciparum H3 (PfH3) was abrogated by histone-specific antibodies. The release of nuclear contents on rupture of infected erythrocytes was captured by live cell imaging and confirmed by detecting nucleosomes in the supernatants of parasite cultures. HeH and recombinant parasite histones also induced endothelial permeability through a charge-dependent mechanism that resulted in disruption of junctional protein expression and cell death. Recombinant human activated protein C cleaved HeH and PfH3 and abrogated their proinflammatory effects. Circulating nucleosomes of both human and parasite origin were detected in the plasma of patients with falciparum malaria and correlated positively with disease severity. These results support a pathogenic role for both host- and pathogen-derived histones in P. falciparum-caused malaria.

Dynamic interactions ofPlasmodiumspp. with vascular endothelium

“…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. 121 In addition, PfHRP2 has been shown to induce redistribution of the tight junction protein claudin-5 leading to compromised integrity of the brain endothelial cell line hCMEC/D3. 113 Although the parasite protein activated caspase 1, apoptosis and pyroptosis were excluded by the absence of DNA fragmentation and the lack of an inhibitory effect of a pan-caspase inhibitor at 6 hours when a change in permeability was first detectable.…”

“…P. falciparum histones H3 and H4, which share >95% homology with human histones, were shown to increase endothelial permeability in primary human lung cells based on their strongly cationic charge. 121 Histone-induced disruption of VE-cadherin, claudin-5 and ZO-1 expression was partially Src family kinase-dependent, and may also involve caspase-independent cell death. In vivo, the direct injection of bovine histones, which share high homology to P. falciparum histones, into murine renal arteries induced TLR2/4-dependent endothelial cell death and edema culminating in acute kidney injury.…”

“…Although hemozoin itself does not induce endothelial barrier dysfunction, 47,49 it has been shown to activate NF-kB signaling pathways as shown by increased IL-8 and MCP-1 (CCL2) production in HUVEC. 118 Other parasite derived products such as DNA, 119,120 histones, 121 tRNA synthetase, 120 uric acid 122 and heat shock proteins (HSP) 123 have been shown to activate the host immune system. In the case of histones, they can disrupt endothelia into renal arteries l barrier function.…”

Parasites in central nervous system

“…Cytoadherence leads to the occurrence of few methods such as the release of endothelial microparticles, apoptosis of host cells and endothelial activation that occur in the brain; the endothelial activation process has an essential role in the pathogenesis of cerebral malaria [27].…”

The role of Vitamin D in malaria

“…Hemozoin induces early cytokine-mediated lysozyme release from human monocytes through p38 MAPK-and NF-ĸB-dependent mechanisms [130]. P. falciparum histones extracted from merozoites directly stimulate the production of IL-8 and other inflammatory mediators by primary human dermal micro-vascular endothelial cells through a signaling pathway that involves the Src family kinases and p38 MAPK [131]. Malaria parasite development in the mosquito is regulated by a conserved MAPK signaling pathway that mediates the effects of an ingested cytokine [132].…”