Adhesion of Plasmodium falciparum -infected erythrocytes to human cells: molecular mechanisms and therapeutic implications
Reads0
Chats0
TLDR
Further research is needed to realise the untapped potential of antiadhesion adjunctive therapies, which could revolutionise the treatment of severe malaria and reduce the high mortality rate of the disease.Abstract:
Severe malaria has a high mortality rate (15–20%) despite treatment with effective antimalarial drugs. Adjunctive therapies for severe malaria that target the underlying disease process are therefore urgently required. Adhesion of erythrocytes infected with Plasmodium falciparum to human cells has a key role in the pathogenesis of life-threatening malaria and could be targeted with antiadhesion therapy. Parasite adhesion interactions include binding to endothelial cells (cytoadherence), rosetting with uninfected erythrocytes and platelet-mediated clumping of infected erythrocytes. Recent research has started to define the molecular mechanisms of parasite adhesion, and antiadhesion therapies are being explored. However, many fundamental questions regarding the role of parasite adhesion in severe malaria remain unanswered. There is strong evidence that rosetting contributes to severe malaria in sub-Saharan Africa; however, the identity of other parasite adhesion phenotypes that are implicated in disease pathogenesis remains unclear. In addition, the possibility of geographic variation in adhesion phenotypes causing severe malaria, linked to differences in malaria transmission levels and host immunity, has been neglected. Further research is needed to realise the untapped potential of antiadhesion adjunctive therapies, which could revolutionise the treatment of severe malaria and reduce the high mortality rate of the disease.read more
Citations
More filters
Journal ArticleDOI
Microglia development and function.
TL;DR: The exciting developments in the understanding of microglial biology are discussed, from their developmental origin to their participation in CNS homeostasis and pathophysiological states such as neuropsychiatric disorders, neurodegeneration, sterile injury responses, and infectious diseases.
Journal ArticleDOI
Severe malaria is associated with parasite binding to endothelial protein C receptor
Louise Turner,Thomas Lavstsen,Sanne S. Berger,Christian W. Wang,Jens E.V. Petersen,Marion Avril,Andrew J. Brazier,Jim Freeth,Jakob S. Jespersen,Morten Nielsen,Pamela Magistrado,John Lusingu,Joseph D. Smith,Joseph D. Smith,Matthew K. Higgins,Thor G. Theander +15 more
TL;DR: EPCR, which mediates the cytoprotective effects of activated protein C, is identified as the endothelial receptor for DC8 and DC13 PfEMP1, and it is shown that EPCR binding is mediated through the amino-terminal cysteine-rich interdomain region (CIDRα1) ofDC8 and group A Pf EMP1 subfamilies, and that CIDR α1 interferes with protein C binding to EPCC.
Journal ArticleDOI
Plasmodium falciparum erythrocyte membrane protein 1 diversity in seven genomes - divide and conquer
Thomas S. Rask,Thomas S. Rask,Daniel Aaen Hansen,Thor G. Theander,Anders Gorm Pedersen,Thomas Lavstsen +5 more
TL;DR: This study redefines and reclassifies the domains of PfEMP1 from seven genomes, and hopes this comprehensive categorization will provide a platform for future studies on var/PfEMP1 expression and function.
Journal ArticleDOI
Plasmodium falciparum erythrocyte membrane protein 1 domain cassettes 8 and 13 are associated with severe malaria in children
Thomas Lavstsen,Louise Turner,Fredy Saguti,Pamela Magistrado,Pamela Magistrado,Thomas S. Rask,Jakob S. Jespersen,Christian W. Wang,Sanne S. Berger,Vito Baraka,Andrea Marion Marquard,Andaine Seguin-Orlando,Eske Willerslev,M. Thomas P. Gilbert,John Lusingu,John Lusingu,Thor G. Theander +16 more
TL;DR: The combined analysis showed that severe malaria syndromes, including severe anemia and cerebral malaria, are associated with high transcript levels of PfEMP1 domain cassette 8-encoding var genes.
Journal ArticleDOI
A subset of group A-like var genes encodes the malaria parasite ligands for binding to human brain endothelial cells.
Antoine Claessens,Yvonne Adams,Ashfaq Ghumra,Gabriella Lindergard,Caitlin C. Buchan,Cheryl Andisi,Peter C. Bull,Sachel Mok,Archna P. Gupta,Christian W. Wang,Louise Turner,Mònica Arman,Ahmed Raza,Zbynek Bozdech,J. Alexandra Rowe +14 more
TL;DR: A binding phenotype for virulence-associated group A P. falciparum erythrocyte membrane protein 1 variants is described and targets for interventions to treat or prevent cerebral malaria are identified.
References
More filters
Journal ArticleDOI
The global distribution of clinical episodes of Plasmodium falciparum malaria
TL;DR: It is estimated that there were 515 (range 300–660) million episodes of clinical P. falciparum malaria in 2002, up to 50% higher than those reported by the World Health Organization and 200% higher for areas outside Africa, reflecting the WHO's reliance upon passive national reporting for these countries.
Journal ArticleDOI
Structure and function of the spleen.
Reina E. Mebius,Georg Kraal +1 more
TL;DR: The spleen enables it to remove older erythrocytes from the circulation and leads to the efficient removal of blood-borne microorganisms and cellular debris, which makes it the most important organ for antibacterial and antifungal immune reactivity.
Journal ArticleDOI
The pathogenic basis of malaria
TL;DR: Insight into the complexity of malaria pathogenesis is vital for understanding the disease and will provide a major step towards controlling it.
Journal ArticleDOI
The large diverse gene family var encodes proteins involved in cytoadherence and antigenic variation of plasmodium falciparum-infected erythrocytes
Xin-zhuan Su,Virginia M. Heatwole,Samuel P. Wertheimer,Frangoise Guinet,Jacqueline A. Herrfeldt,David S. Peterson,Jeffrey A. Ravetch,Thomas E. Wellems +7 more
TL;DR: A large and extremely diverse family of P. falciparum genes (var) that encode 200-350 kDa proteins having the expected properties of antigenically variant adhesion molecules are described.
Journal ArticleDOI
Severe falciparum malaria.
TL;DR: Children having pulmonary edema, shock and cerebral malaria had high case fatality rate and over all mortality was 9.9%, cerebral malaria being the commonest cause and multi-system involvement was seen in 58.4% cases of death.
Related Papers (5)
P. falciparum rosetting mediated by a parasite-variant erythrocyte membrane protein and complement-receptor 1
Genome sequence of the human malaria parasite Plasmodium falciparum
Malcolm J. Gardner,Neil Hall,Eula Fung,Owen White,Matthew Berriman,Richard W. Hyman,Jane M. Carlton,Arnab Pain,Karen E. Nelson,Sharen Bowman,Ian T. Paulsen,Keith D. James,Jonathan A. Eisen,Kim Rutherford,Steven L. Salzberg,Alister Craig,Sue Kyes,Man Suen Chan,Vishvanath Nene,Shamira J. Shallom,Bernard B. Suh,Jeremy Peterson,Samuel V. Angiuoli,Mihaela Pertea,Jonathan E. Allen,Jeremy D. Selengut,Daniel H. Haft,Michael W. Mather,Akhil B. Vaidya,David M. A. Martin,Alan H. Fairlamb,Martin Fraunholz,David S. Roos,Stuart A. Ralph,Geoffrey I. McFadden,Leda M. Cummings,G. Mani Subramanian,Christopher J. Mungall,J. Craig Venter,Daniel J. Carucci,Stephen L. Hoffman,Chris I. Newbold,Ronald W. Davis,Claire M. Fraser,Bart Barrell +44 more