A family affair: var genes, PfEMP1 binding, and malaria disease

Kraemer, Susan M.; Smith, Joseph D.

doi:10.1016/j.mib.2006.06.006

Cited by 259 publications

(233 citation statements)

References 48 publications

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“…The PfEMP1 family is encoded by 50-60 var genes per parasite isolate (12). Although the sequence of each var gene is unique, all variants start with an Nterminal segment (NTS) and are followed by a succession of Duffy binding-like (DBL) and cysteine-rich interdomain region (CIDR) domains.…”

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confidence: 99%

“…These domains can be categorized into subtypes by the presence of short, conserved amino acid motifs, the rest of the sequence being highly polymorphic (13). The var gene family is subdivided into three main subgroups, A, B, and C, based on semiconserved upstream sequences (12). All group A var genes are located near the telomeres, all group C var genes are near the centromeres, and group B var genes can be found in either location.…”

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confidence: 99%

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A subset of group A-like var genes encodes the malaria parasite ligands for binding to human brain endothelial cells

Claessens

Adams

Ghumra

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

197

230

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Cerebral malaria is the most deadly manifestation of infection with Plasmodium falciparum. The pathology of cerebral malaria is characterized by the accumulation of infected erythrocytes (IEs) in the microvasculature of the brain caused by parasite adhesins on the surface of IEs binding to human receptors on microvascular endothelial cells. The parasite and host molecules involved in this interaction are unknown. We selected three P. falciparum strains (HB3, 3D7, and IT/FCR3) for binding to a human brain endothelial cell line (HBEC-5i). The whole transcriptome of isogenic pairs of selected and unselected parasites was analyzed using a variant surface antigen-supplemented microarray chip. After selection, the most highly and consistently up-regulated genes were a subset of group A-like var genes (HB3var3, 3D7_PFD0020c, ITvar7, and ITvar19) that showed 11-to >100-fold increased transcription levels. These var genes encode P. falciparum erythrocyte membrane protein (PfEMP)1 variants with distinct N-terminal domain types (domain cassette 8 or domain cassette 13). Antibodies to HB3var3 and PFD0020c recognized the surface of live IEs and blocked binding to HBEC-5i, thereby confirming the adhesive function of these variants. The clinical in vivo relevance of the HBEC-selected parasites was supported by significantly higher surface recognition of HBEC-selected parasites compared with unselected parasites by antibodies from young African children suffering cerebral malaria (Mann-Whitney test, P = 0.029) but not by antibodies from controls with uncomplicated malaria (Mann-Whitney test, P = 0.58). This work describes a binding phenotype for virulence-associated group A P. falciparum erythrocyte membrane protein 1 variants and identifies targets for interventions to treat or prevent cerebral malaria.adherence | pathogenesis | sequestration

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confidence: 99%

mentioning

confidence: 99%

A subset of group A-like var genes encodes the malaria parasite ligands for binding to human brain endothelial cells

Claessens

Adams

Ghumra

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

197

230

View full text Add to dashboard Cite

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“…The DBL protein fold is unique to Plasmodium and is able to recognize and tightly bind a diverse array of host cell receptors. In addition to their critical role during invasion, DBL domains also mediate microvasculature adherence of infected erythrocytes by erythrocyte membrane protein 1 (PfEMP1), a phenomenon directly associated with severe malaria (7).…”

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confidence: 99%

Crystal and Solution Structures of Plasmodium falciparum Erythrocyte-binding Antigen 140 Reveal Determinants of Receptor Specificity during Erythrocyte Invasion

Lin¹,

Malpede²,

Batchelor

et al. 2012

Journal of Biological Chemistry

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Background:The malaria parasite Plasmodium falciparum utilizes PfEBA-140 to invade host erythrocytes. Results: The minimal binding region of PfEBA-140 contains unique structural components compared with other Plasmodium invasion ligands. Conclusion: Distinct structural and mechanistic elements of PfEBA-140 binding are likely determinants of receptor specificity. Significance: This study provides the first view into the basis of receptor specificity of P. falciparum invasion ligands.

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“…Por outro lado, indivíduos com grau leve da infecção ou sem complicações, tipicamente apresentam febre e sintomas como: arrepios, suores, dor de cabeça, vômito, diarréia, anemia, icterícia e inchaço do baço (esplenomegalia) (BAUMEISTER et al, 2006;CHAKRAVORTY;CRAIG, 2005;DEPLAINE et al, 2011;GROBUSCH;KREMSNER, 2005;KIRK et al, 2005;SALIBA, 2007;KRAEMER;SMITH, 2006;LAISHRAM et al, 2012;LAUER et al, 1997;ROWE et al, 2009). Quando diagnosticada corretamente e tratada as chances de cura são elevadas (BAUMEISTER et al, 2006;CHAKRAVORTY;CRAIG, 2005;DEPLAINE et al, 2011;GROBUSCH;KREMSNER, 2005;KIRK et al, 2005;SALIBA, 2007;KRAEMER;SMITH, 2006;LAISHRAM et al, 2012;LAUER et al, 1997;ROWE et al, 2009), mas o acúmulo de eritrócitos infectados em microvasos causa considerável obstrução do fluxo sanguíneo, diminuição da perfusão e remoção de resíduos dos tecidos com consequentes danos aos órgãos vitais como cérebro, pulmão, fígado, intestino e pele (MILLER, LOUIS H. et al, 2002). A síndrome cerebral parece ser responsável pela maioria das mortes e é caracterizada por coma e muitas vezes com convulsões, mas qualquer grau de comprometimento da consciência pode indicar o envolvimento cerebral (BEESON; BROWN, 2002;MENENDEZ;FLEMING;ALONSO, 2000;PONSFORD et al, 2012;RÉNIA et al, 2012).…”

Section: Bbr -Biochemistry and Biotechnology Reportsunclassified

Malária: Dos velhos fármacos aos novos alvos moleculares

Leite¹,

Fonseca²,

Nunes³

et al. 2013

BBR - Biochem. Biotechnol.

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Malaria is a parasite disease that most affects humans with a global impact, without an effective treatment. According to the World Health Organization (WHO), the absence of a new therapeutic alternative, soon all strains will be resistant to current drugs. This study reports historical aspects, biological life cycle, current drugs, molecular targets able to therapeutic intervention and recent pharmacological receptors. This review concludes with a brief discussion of the prospects and difficulties contributing for advance for new antimalarials development. Keywords RESUMOMalária é a doença parasitária que mais acomete o homem. Segundo a Organização Mundial de Saúde (OMS), o aparecimento de cepas de Plasmodium resistentes a artemisinina tornam a busca de novos alvos e compostos com ação antimalárica extremamente necessária. Neste estudo relatamos aspectos históricos, ciclo biológico, atuais fármacos, alvos moleculares passíveis de intervenção terapêutica e recentes receptores farmacológicos. Esta revisão conclui com uma breve discussão das perspectivas e dificuldades contribuindo para o avanço no desenvolvimento de novos antimaláricos. Palavras-chave:PfHT, PfATPase, modelagem molecular, desenvolvimento de fármacos.

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A family affair: var genes, PfEMP1 binding, and malaria disease

Cited by 259 publications

References 48 publications

A subset of group A-like var genes encodes the malaria parasite ligands for binding to human brain endothelial cells

A subset of group A-like var genes encodes the malaria parasite ligands for binding to human brain endothelial cells

Crystal and Solution Structures of Plasmodium falciparum Erythrocyte-binding Antigen 140 Reveal Determinants of Receptor Specificity during Erythrocyte Invasion

Malária: Dos velhos fármacos aos novos alvos moleculares

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