Parasite histones are toxic to brain endothelium and link blood barrier breakdown and thrombosis in cerebral malaria

Abstract

Microvascular thrombosis and blood–brain barrier (BBB) breakdown are key components of cerebral malaria (CM) pathogenesis in African children and are implicated in fatal brain swelling. How Plasmodium falciparum infection causes this endothelial disruption and why this occurs, particularly in the brain, is not fully understood. In this study, we have demonstrated that circulating extracellular histones, equally of host and parasite origin, are significantly elevated in CM patients. Higher histone levels are associated with brain swelling on magnetic resonance imaging. On postmortem brain sections of CM patients, we found that histones are colocalized with P falciparum–infected erythrocytes sequestered inside small blood vessels, suggesting that histones might be expelled locally during parasite schizont rupture. Histone staining on the luminal vascular surface colocalized with thrombosis and leakage, indicating a possible link between endothelial surface accumulation of histones and coagulation activation and BBB breakdown. Supporting this, patient sera or purified P falciparum histones caused disruption of barrier function and were toxic to cultured human brain endothelial cells, which were abrogated with antihistone antibody and nonanticoagulant heparin. Overall, our data support a role for histones of parasite and host origin in thrombosis, BBB breakdown, and brain swelling in CM, processes implicated in the causal pathway to death. Neutralizing histones with agents such as nonanticoagulant heparin warrant exploration to prevent brain swelling in the development or progression of CM and thereby to improve outcomes.

Plasma angiopoietin-2 is associated with age-related deficits in cognitive sub-scales in Ugandan children following severe malaria

“…An increase in vascular permeability may facilitate parasite antigens like histidine-rich protein-2 crossing the blood–brain-barrier [ 34 ], resulting in an increase in neuro-inflammation [ 35 , 36 ], neuro-active metabolites [ 37 ], and axonal injury [ 38 ]. Other bioactive parasite products (i.e., parasite histones) may also contribute to vascular thrombosis and vascular leak [ 39 ]. Increased availability of more advanced magnetic resonance imaging (MRI) techniques in low-and-middle-income settings may yield important insights into structural and functional brain changes across the spectrum of uncomplicated malaria, to severe (non-cerebral malaria) and cerebral malaria [ 40 ].…”

Unveiling the Sugary Secrets of Plasmodium Parasites

“…Heparin-like molecules also proved beneficial against bloodbrain barrier (BBB) breakdown in an in vitro model of cerebral malaria (Moxon et al, 2020). Accumulation of parasite and RBC histones at the brain endothelium, likely released during schizont rupture, leads to BBB disruption.…”

“…Accumulation of parasite and RBC histones at the brain endothelium, likely released during schizont rupture, leads to BBB disruption. HLMs prevent histone-induced BBB breakdown, suggesting yet another pathway for therapeutic application of HLMs (Moxon et al, 2020).…”

Extracellular histones stimulate collagen expressionin vitroand promote liver fibrogenesis in a mouse modelviathe TLR4-MyD88 signaling pathway

“…During tissue damage and cell death, nuclear chromatin is cleaved into nucleosomes that are released extracellularly[ 37 ] and further degraded into individual histones[ 38 ]. Although histones are rapidly cleared by the liver[ 39 ] and rarely detected in blood[ 25 , 26 , 31 , 32 ], liver cell death is likely to release histones locally[ 40 - 43 ], which stimulate adjacent cells, including HSCs. Histones can activate TLR2, TLR4 and TLR9[ 24 , 40 , 43 - 46 ] in the early stage of chronic liver injury and fibrogenesis.…”