Cerebral malaria is associated with differential cytoadherence to brain endothelial cells

Storm, Janet; Jespersen, Jakob S.; Seydel, Karl B.; Szestak, Tadge; Mbewe, Maurice; Chisala, Ngawina V.; Phula, Patricia; Wang, Christian W.; Taylor, Terrie E.; Moxon, Christopher A.; Lavstsen, Thomas; Craig, Alister G.

doi:10.15252/emmm.201809164

Cited by 106 publications

(124 citation statements)

References 94 publications

(202 reference statements)

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“…Individual domains of PfEMP-1 bind to different receptors on endothelial cells, of which intercellular adhesion protein-1 (ICAM-1), endothelial protein C receptor (EPCR), and CD36 are the most prominent (Turner et al, 2013;Hsieh et al, 2016). Recently, it was shown that pRBCs from patients with cerebral malaria bind at higher rates to brain endothelial cells than those from patients with uncomplicated malaria (Storm et al, 2019). Interestingly, using an engineered three-dimensional human endothelial microvessel model, it was also demonstrated that pRBC binding is heterogeneous and depends on the expressed type of PfEMP-1 as well as on several physiological variables, such as blood flow speed and endothelial preactivation by TNF-α (Bernabeu et al, 2019).…”

Section: (A) Plasmodium Falciparummentioning

confidence: 99%

Microglia in neuropathology caused by protozoan parasites

et al. 2019

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Involvement of the central nervous system (CNS) is the most severe consequence of some parasitic infections. Protozoal infections comprise a group of diseases that together affect billions of people worldwide and, according to the World Health Organization, are responsible for more than 500000 deaths annually. They include African and American trypanosomiasis, leishmaniasis, malaria, toxoplasmosis, and amoebiasis. Mechanisms underlying invasion of the brain parenchyma by protozoa are not well understood and may depend on parasite nature: a vascular invasion route is most common. Immunosuppression favors parasite invasion into the CNS and therefore the host immune response plays a pivotal role in the development of a neuropathology in these infectious diseases. In the brain, microglia are the resident immune cells active in defense against pathogens that target the CNS. Beside their direct role in innate immunity, they also play a principal role in coordinating the trafficking and recruitment of other immune cells from the periphery to the CNS. Despite their evident involvement in the neuropathology of protozoan infections, little attention has given to microglia–parasite interactions. This review describes the most prominent features of microglial cells and protozoan parasites and summarizes the most recent information regarding the reaction of microglial cells to parasitic infections. We highlight the involvement of the periphery–brain axis and emphasize possible scenarios for microglia–parasite interactions.

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Section: (A) Plasmodium Falciparummentioning

confidence: 99%

Microglia in neuropathology caused by protozoan parasites

et al. 2019

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“…We also observed early acquisition of IgG specific for CIDRα1.8 domains. Expression of these domains, as well as EPCR-binding CIDRα1 domains in general, is associated with severe malaria including cerebral malaria in African children (18-21, 45) and Indian adults (46).…”

Section: Discussionmentioning

confidence: 99%

Longitudinal analysis of naturally acquired antibodies to PfEMP1 CIDR domain variants and their association with malaria protection

Obeng-Adjei

Larremore

Turner

et al. 2020

Preprint

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Malaria pathogenicity is determined, in part, by the adherence of Plasmodium falciparum infected erythrocytes to the microvasculature mediated via specific interactions between PfEMP1 variant domains to host endothelial receptors. Naturally acquired antibodies against specific PfEMP1 variants can play an important role in clinical protection against malaria. We evaluated IgG responses against a repertoire of PfEMP1 CIDR domain variants to determine the rate and order of variant-specific antibody acquisition and their association with protection against febrile malaria in a prospective cohort study conducted in an area of intense, seasonal malaria transmission. Using longitudinal data, we found that IgG to the pathogenic domain variants CIDRα1.7 and CIDRα1.8 were acquired the earliest. Furthermore, IgG to CIDRγ3 was associated with reduced prospective risk of febrile malaria and recurrent malaria episodes. Future studies will need to validate these findings in other transmission settings and determine the functional activity of these naturally acquired CIDR variant-specific antibodies.

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“…Secondly, parasite variants associated with the development of CM (expressing domain cassette 8 [DC8]) reduce aPC production, by binding to EPCR and inhibiting its activity (52). DC8 variants also show a tropism for brain endothelium (34, 52, 53). Hence parasites in CM patients may be more likely to concentrate plasmodial histones in the brain, through sequestration, and simultaneously may prevent their breakdown, through inhibiting aPC production.…”

Section: Discussionmentioning

confidence: 99%

Parasite histones mediate leak and coagulopathy in cerebral malaria

Moxon

Alhamdi

Storm

et al. 2019

Preprint

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Coagulopathy and leak, specific to the brain vasculature, are central pathogenetic 43 components of cerebral malaria (CM). It is unclear how the parasite, Plasmodium falciparum, 44 triggers these processes. Extracellular histones, released from damaged host cells, bind to cell 45 membranes and cause coagulation activation, platelet aggregation and vascular leak in 46 diverse critical illnesses. In CM patients with P. falciparum, serum histones correlate with 47 fibrin formation, thrombocytopenia, and endothelial activation and predict brain swelling on 48 magnetic resonance imaging and fatal outcome. Post-mortem, histones bind to the luminal 49 vascular surface, co-localizing with P. falciparum-infected erythrocytes (IE), and with 50 thrombosis and leak. Purified P. falciparum histones cause toxicity and barrier disruption in 51 cultured human brain microvascular endothelial cells, as does serum from CM patients, 52 reversed by anti-histone antibodies and non-anticoagulant heparin. These data implicate 53 parasite histones as a key trigger of fatal brain swelling in CM. Neutralizing histones with 54agents such as non-anticoagulant heparin warrant exploration to prevent brain swelling and 55 improve outcome.

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Cerebral malaria is associated with differential cytoadherence to brain endothelial cells

Cited by 106 publications

References 94 publications

Microglia in neuropathology caused by protozoan parasites

Microglia in neuropathology caused by protozoan parasites

Longitudinal analysis of naturally acquired antibodies to PfEMP1 CIDR domain variants and their association with malaria protection

Parasite histones mediate leak and coagulopathy in cerebral malaria

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