Pathogenicity Determinants of the Human Malaria Parasite Plasmodium falciparum Have Ancient Origins

Brazier, Andrew J.; Avril, Marion; Bernabeu, Maria; Benjamin, Maxwell; Smith, Joseph D.

doi:10.1128/msphere.00348-16

Cited by 12 publications

(9 citation statements)

References 63 publications

(130 reference statements)

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“…Our central finding here is that PfEMP1 variants linked to severe malaria display extensive heterogeneity in binding activity for resting and activated 3D brain microvessels, and differences are at least partially attributable to their combinatorial binding properties for EPCR and ICAM-1. Although EPCR binding appears to be an ancient parasite adhesion trait that has been retained within the PfEMP1 family across the large time span that separates human and chimpanzee malaria species (9, 49), and several studies have converged toward its importance for parasite cytoadhesion (10, 13, 14, 26, 35, 36), it recently has been questioned whether EPCR is a physiological endothelial receptor for P. falciparum (40).…”

Section: Discussionmentioning

confidence: 99%

Binding Heterogeneity of Plasmodium falciparum to Engineered 3D Brain Microvessels Is Mediated by EPCR and ICAM-1

Bernabeu¹,

Gunnarsson

Vishnyakova³

et al. 2019

mBio

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Cerebral malaria is a severe neurological complication associated with sequestration ofPlasmodium falciparum-infected erythrocytes (IE) in the brain microvasculature, but the specific binding interactions remain under debate. Here, we have generated an engineered three-dimensional (3D) human brain endothelial microvessel model and studiedP. falciparumbinding under the large range of physiological flow velocities that occur in both health and disease. Perfusion assays on 3D microvessels reveal previously unappreciated phenotypic heterogeneity in parasite binding to tumor necrosis factor alpha (TNF-α)-activated brain endothelial cells. While clonal parasite lines expressing a group BP. falciparumerythrocyte membrane protein 1 (PfEMP1) present an increase in binding to activated 3D microvessels,P. falciparum-IE expressing DC8-PfEMP1 present a decrease in binding. The differential response to endothelium activation is mediated by surface expression changes of endothelial protein C receptor (EPCR) and intercellular adhesion molecule 1 (ICAM-1). These findings demonstrate heterogeneity in parasite binding and provide evidence for a parasite strategy to adapt to a changing microvascular environment during infection. The engineered 3D human brain microvessel model provides new mechanistic insight into parasite binding and opens opportunities for further studies on malaria pathogenesis and parasite-vessel interactions.IMPORTANCECerebral malaria research has been hindered by the inaccessibility of the brain. Here, we have developed an engineered 3D human brain microvessel model that mimics the blood flow rates and architecture of small blood vessels to study howP. falciparum-infected human erythrocytes attach to brain endothelial cells. By studying parasite lines with different adhesive properties, we show that the malaria parasite binding rate is heterogeneous and strongly influenced by physiological differences in flow and whether the endothelium has been previously activated by TNF-α, a proinflammatory cytokine that is linked to malaria disease severity. We also show the importance of human EPCR and ICAM-1 in parasite binding. Our model sheds new light on howP. falciparumbinds within brain microvessels and provides a powerful method for future investigations of recruitment of human brain pathogens to the blood vessel lining of the brain.

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Section: Discussionmentioning

confidence: 99%

Binding Heterogeneity of Plasmodium falciparum to Engineered 3D Brain Microvessels Is Mediated by EPCR and ICAM-1

Bernabeu¹,

Gunnarsson

Vishnyakova³

et al. 2019

mBio

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“…Of these, the gorilla P. falciparum became adapted to human by zoonotic transfer about 50,000 YBP. The pathogenicity of P. falciparum arises from adhesion domains in the var gene family that allow entrapment of infected red cells in the microcirculation; the var genes originated before their great ape hosts, suggesting ancient evolutionary battles of host resistance and Plasmodium genes that modify red cell adhesion and virulence (Brazier et al 2017).…”

Section: Population Density and Epidemicsmentioning

confidence: 99%

The Exposome in Human Evolution: From Dust to Diesel

Trumble¹,

Finch²

2019

The Quarterly Review of Biology

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Global exposures to air pollution and cigarette smoke are novel in human evolutionary history and are associated with about 16 million premature deaths per year. We investigate the history of the human exposome for relationships between novel environmental toxins and genetic changes during human evolution in six phases. Phase I: With increased walking on savannas, early human ancestors inhaled crustal dust, fecal aerosols, and spores; carrion scavenging introduced new infectious pathogens. Phase II: Domestic fire exposed early Homo to novel toxins from smoke and cooking. Phases III and IV: Neolithic to preindustrial Homo sapiens incurred infectious pathogens from domestic animals and dense communities with limited sanitation. Phase V: Industrialization introduced novel toxins from fossil fuels, industrial chemicals, and tobacco at the same time infectious pathogens were diminishing. Thereby, pathogen-driven causes of mortality were replaced by chronic diseases driven by sterile inflammogens, exogenous and endogenous. Phase VI: Considers future health during global warming with increased air pollution and infections. We hypothesize that adaptation to some ancient toxins persists in genetic variations associated with inflammation and longevity.

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“…In humans, P. falciparum invades erythrocytes, causing them to express a surface protein, P. falciparum erythrocyte membrane protein 1 (PfEMP-1), which is responsible for erythrocyte congestion and sequestration in the brain capillaries (Horata et al, 2009 ; Dorovini-Zis et al, 2011 ). This protein causes the infected erythrocyte to adhere to the endothelial membrane via the CD36 receptor and EPCR, consequently leading to the severity of cerebral malaria (Turner et al, 2013 ; Almelli et al, 2014 ; Bernabeu et al, 2016 ; Brazier et al, 2017 ). Erythrocyte sequestration in the brain was also observed in association with axonal and myelin damage, blood-brain barrier (BBB) disruption, coma and cellular immune responses, such as fibrin–platelet thrombi, intravascular accumulation of hemozoin–containing CD45/CD68-positive monocytes, necrosis of the endothelial lining of the occluded vessel and perivascular hemorrhage (Dorovini-Zis et al, 2011 ; Ponsford et al, 2012 ).…”

Section: Malaria: General Overviewmentioning

confidence: 99%

Could Heme Oxygenase-1 Be a New Target for Therapeutic Intervention in Malaria-Associated Acute Lung Injury/Acute Respiratory Distress Syndrome?

Pereira

Marinho

Epiphânio

2018

Front. Cell. Infect. Microbiol.

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Malaria is a serious disease and was responsible for 429,000 deaths in 2015. Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is one of the main clinical complications of severe malaria; it is characterized by a high mortality rate and can even occur after antimalarial treatment when parasitemia is not detected. Rodent models of ALI/ARDS show similar clinical signs as in humans when the rodents are infected with murine Plasmodium. In these models, it was shown that the induction of the enzyme heme oxygenase 1 (HO-1) is protective against severe malaria complications, including cerebral malaria and ALI/ARDS. Increased lung endothelial permeability and upregulation of VEGF and other pro-inflammatory cytokines were found to be associated with malaria-associated ALI/ARDS (MA-ALI/ARDS), and both were reduced after HO-1 induction. Additionally, mice were protected against MA-ALI/ARDS after treatment with carbon monoxide- releasing molecules or with carbon monoxide, which is also released by the HO-1 activity. However, high HO-1 levels in inflammatory cells were associated with the respiratory burst of neutrophils and with an intensification of inflammation during episodes of severe malaria in humans. Here, we review the main aspects of HO-1 in malaria and ALI/ARDS, presenting the dual role of HO-1 and possibilities for therapeutic intervention by modulating this important enzyme.

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Pathogenicity Determinants of the Human Malaria Parasite Plasmodium falciparum Have Ancient Origins

Cited by 12 publications

References 63 publications

Binding Heterogeneity of Plasmodium falciparum to Engineered 3D Brain Microvessels Is Mediated by EPCR and ICAM-1

Binding Heterogeneity of Plasmodium falciparum to Engineered 3D Brain Microvessels Is Mediated by EPCR and ICAM-1

The Exposome in Human Evolution: From Dust to Diesel

Could Heme Oxygenase-1 Be a New Target for Therapeutic Intervention in Malaria-Associated Acute Lung Injury/Acute Respiratory Distress Syndrome?

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