Pathogenetic mechanisms and treatment targets in cerebral malaria

Hadjilaou, Alexandros; Brandi, Johannes; Riehn, Mathias; Friese, Manuel A.; Jacobs, Thomas

doi:10.1038/s41582-023-00881-4

Cited by 13 publications

(5 citation statements)

References 342 publications

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“…Cerebral malaria is a multifactorial disease that has been extensively investigated, although many questions remain regarding its pathogenesis. A view of CM pathology has emerged in recent years that proposes dysregulation of coagulation pathways, inflammation, release of parasite factors from mature IE, and the sequestration of IE in the vasculature all contribute to endothelial dysfunction and, ultimately, the breakdown of the BBB 8,9,49 . Cytoadhesion of IE to endothelial cells is one of the events in a multi-step process leading to localized accumulation of both IE and RBC, and rupture and release of parasite and intercellular erythrocyte components and soluble factors, resulting in activation of the endothelium and immune responses, compromising BBB integrity 20,50 .…”

Section: Discussionmentioning

confidence: 99%

Transcriptional responses of brain endothelium toPlasmodium falciparumpatient-derived isolatesin vitro

Askonas,

Storm,

Camarda

et al. 2024

Preprint

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A hallmark of cerebral malaria is sequestration of Plasmodium falciparum infected erythrocytes (IE) within the brain microvasculature. Binding of IE to endothelium reduces microvascular flow and combined with an inflammatory response perturbs endothelial barrier function, resulting in breakdown of the blood-brain barrier (BBB). Furthermore, cytoadherence leads to activation of the endothelium and alters a range of cell processes affecting signalling pathways, receptor expression, coagulation, and disruption of BBB integrity. Here, we investigated whether cerebral malaria (CM) derived parasites elicit differential effects on human brain microvascular endothelial cells (HBMECs), as compared to uncomplicated malaria (UM) derived parasites. Patient-derived IE from UM and CM clinical cases, as well as non-binding skeleton-binding protein 1 knockout parasites, were overlaid onto TNF-activated HBMECs in a co-culture system. Gene expression analysis of endothelial responses was performed using Fluidigm probe-based assays of a panel of genes involved in inflammation, apoptosis, endothelial barrier function, and the prostacyclin synthesis pathway. We observed a significant effect on the endothelial transcriptional response in the presence of IE, yet there was no significant correlation between HBMEC responses and the type of clinical syndrome (UM or CM). Further, there was no correlation between HBMEC gene expression and both binding itself and the level of IE binding to HBMEC, as we detected the same change in endothelial responses when employing both binding and non-binding parasites. Our results suggest that interaction of IE with endothelial cells in this co-culture model induce some endothelial responses that are independent of clinical origin and independent of the expression of the major variant antigen PfEMP1 on the IE surface.

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Section: Discussionmentioning

confidence: 99%

Transcriptional responses of brain endothelium toPlasmodium falciparumpatient-derived isolatesin vitro

Askonas,

Storm,

Camarda

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…As leukocytes and platelets are recruited and activated, a local proinflammatory cycle ensues; with a positive feedback loop of EC activation, leukocyte/platelet sequestration, and parasite accumulation. All these actions result in microvascular obstruction, altered blood circulation, local ischemia of brain tissue, triggered inflammatory cascades, increased cerebrovascular damage, increased vascular permeability, and further aggravated brain edema ( Turner et al, 2013 ; Hadjilaou et al, 2023 ; Silva-Pedrosa et al, 2023 ). The interactions also induce apoptosis of ECs, leading to the destruction of the BBB.…”

Section: Discussionmentioning

confidence: 99%

Oral administration of IPI549 protects mice from neuropathology and an overwhelming inflammatory response during experimental cerebral malaria

Jin,

Pang,

Zhao

et al. 2024

International Journal for Parasitology: Drugs and Drug Resistan

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“…A view of CM pathology has emerged in recent years that proposes that dysregulation of coagulation pathways, inflammation, release of parasite factors from mature IE, and sequestration of IE in the vasculature all contribute to endothelial dysfunction and breakdown of the BBB ( 8 , 9 , 35 ). Cytoadhesion of IE to endothelial cells is one of the events in a multi-step process leading to localized accumulation of both IE and RBC, as well as rupture and release of parasite and intercellular erythrocyte components and soluble factors, resulting in activation of the endothelium and immune responses, compromising BBB integrity ( 20 , 36 ).…”

Section: Discussionmentioning

confidence: 99%

Transcriptional responses of brain endothelium to Plasmodium falciparum patient-derived isolates in vitro

Askonas,

Storm,

Camarda

et al. 2024

Microbiol Spectr

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A hallmark of cerebral malaria (CM) is sequestration of Plasmodium falciparum -infected erythrocytes (IE) within the brain microvasculature. Binding of IE to endothelium reduces microvascular flow and, combined with an inflammatory response, perturbs endothelial barrier function, resulting in breakdown of the blood-brain barrier (BBB). Cytoadherence leads to activation of the endothelium and alters a range of cell processes affecting signaling pathways, receptor expression, coagulation, and disruption of BBB integrity. Here, we investigated whether CM-derived parasites elicit differential effects on human brain microvascular endothelial cells (HBMECs), as compared to uncomplicated malaria (UM)-derived parasites. Patient-derived IE from UM and CM clinical cases, as well as non-binding skeleton-binding protein 1 knockout parasites, were overlaid onto tumour necrosis factor (TNF)-activated HBMECs. Gene expression analysis of endothelial responses was performed using probe-based assays of a panel of genes involved in inflammation, apoptosis, endothelial barrier function, and prostacyclin synthesis pathway. We observed a significant effect on endothelial transcriptional responses in the presence of IE, yet there was no significant correlation between HBMEC responses and type of clinical syndrome (UM or CM). Furthermore, there was no correlation between HBMEC gene expression and both binding itself and level of IE binding to HBMECs, as we detected the same change in endothelial responses when employing both binding and non-binding parasites. Our results suggest that interaction of IE with endothelial cells in this co-culture model induces some endothelial responses that are independent of clinical origin and independent of the expression of the major variant antigen Plasmodium falciparum erythrocyte membrane protein 1 on the IE surface. IMPORTANCE Cerebral malaria (CM) is the most prevalent and deadly complication of severe Plasmodium falciparum infection. A hallmark of this disease is sequestration of P. falciparum -infected erythrocytes (IE) in brain microvasculature that ultimately results in breakdown of the blood-brain barrier. Here, we compared the effect of P. falciparum parasites derived from uncomplicated malaria (UM) and CM cases on the relative gene expression of human brain microvascular endothelial cells (HBMECs) for a panel of genes. We observed a significant effect on the endothelial transcriptional response in the presence of IE, yet there is no significant correlation between HBMEC responses and the type of clinical syndrome (UM or CM). Furthermore, there was no correlation between HBMEC gene expression and both binding itself and the level of IE binding to HBMECs. Our results suggest that interaction of IE with endothelial cells induces endothelial responses that are independent of clinical origin and not entirely driven by surface Plasmodium falciparum erythrocyte membrane protein 1 expression.

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Pathogenetic mechanisms and treatment targets in cerebral malaria

Cited by 13 publications

References 342 publications

Transcriptional responses of brain endothelium toPlasmodium falciparumpatient-derived isolatesin vitro

Transcriptional responses of brain endothelium toPlasmodium falciparumpatient-derived isolatesin vitro

Oral administration of IPI549 protects mice from neuropathology and an overwhelming inflammatory response during experimental cerebral malaria

Transcriptional responses of brain endothelium to Plasmodium falciparum patient-derived isolates in vitro

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