scholarly journals Expressed var genes are found in Plasmodium falciparum subtelomeric regions.

1997 ◽  
Vol 17 (2) ◽  
pp. 604-611 ◽  
Author(s):  
R Hernandez-Rivas ◽  
D Mattei ◽  
Y Sterkers ◽  
D S Peterson ◽  
T E Wellems ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Antigenic Variation ◽  
Protein Product ◽  
Terminal Segment ◽  
Surface Proteins ◽  
Var Genes ◽  
Active Expression ◽  
Transmembrane Sequence ◽  
High Level ◽  
Carboxy Terminal

The antigenic variation and cytoadherence of Plasmodium falciparum-infected erythrocytes are modulated by a family of variant surface proteins encoded by the var multigene family. The var genes occur on multiple chromosomes, often in clusters, and 50 to 150 genes are estimated to be present in the haploid parasite genome. Transcripts from var genes have been previously mapped to internal chromosome positions, but the generality of such assignments and the expression sites and mechanisms that control switches of var gene expression are still in early stages of investigation. Here we describe investigations of closely related var genes that occur in association with repetitive elements near the telomeres of P. falciparum chromosomes. DNA sequence analysis of one of these genes (FCR3-varT11-1) shows the characteristic two-exon structure encoding expected var features, including three variable Duffy binding-like (DBL) domains, a transmembrane sequence, and a carboxy-terminal segment thought to anchor the protein product in knobs at the surface of the parasitized erythrocyte. FCR3-varT11-1 cross-hybridizes with var genes located close to the telomeres of many other P. falciparum chromosomes, including a transcribed gene (FCR3-varT3-1) in chromosome 3 of the P. falciparum FCR3 line. The relatively high level transcription from this gene shows that the polymorphic chromosome ends of P. falciparum, which have been proposed to be transcriptionally silent, can be active expression sites for var genes. The pattern of the FCR3-varT11-1 and FCR3-varT3-1 genes are variable between different P. falciparum lines, presumably due to DNA rearrangements. Thus, recombination events in subtelomeric DNA may have a role in the expression of novel var forms.

scholarly journals CRISPR/Cas9 Genome Editing Reveals That the Intron Is Not Essential for var2csa Gene Activation or Silencing in Plasmodium falciparum

mBio ◽  
2017 ◽  
Vol 8 (4) ◽  
Author(s):  
Jessica M. Bryant ◽  
Clément Regnault ◽  
Christine Scheidig-Benatar ◽  
Sebastian Baumgarten ◽  
Julien Guizetti ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Transcriptional Regulation ◽  
Gene Family ◽  
Genome Editing ◽  
Immune Evasion ◽  
Antigenic Variation ◽  
Surface Proteins ◽  
Functional Study ◽  
Monoallelic Expression ◽  
Immune Evasion Mechanism

ABSTRACT Plasmodium falciparum relies on monoallelic expression of 1 of 60 var virulence genes for antigenic variation and host immune evasion. Each var gene contains a conserved intron which has been implicated in previous studies in both activation and repression of transcription via several epigenetic mechanisms, including interaction with the var promoter, production of long noncoding RNAs (lncRNAs), and localization to repressive perinuclear sites. However, functional studies have relied primarily on artificial expression constructs. Using the recently developed P. falciparum clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system, we directly deleted the var2csa P. falciparum 3D7_1200600 (Pf3D7_1200600) endogenous intron, resulting in an intronless var gene in a natural, marker-free chromosomal context. Deletion of the var2csa intron resulted in an upregulation of transcription of the var2csa gene in ring-stage parasites and subsequent expression of the PfEMP1 protein in late-stage parasites. Intron deletion did not affect the normal temporal regulation and subsequent transcriptional silencing of the var gene in trophozoites but did result in increased rates of var gene switching in some mutant clones. Transcriptional repression of the intronless var2csa gene could be achieved via long-term culture or panning with the CD36 receptor, after which reactivation was possible with chondroitin sulfate A (CSA) panning. These data suggest that the var2csa intron is not required for silencing or activation in ring-stage parasites but point to a subtle role in regulation of switching within the var gene family. IMPORTANCE Plasmodium falciparum is the most virulent species of malaria parasite, causing high rates of morbidity and mortality in those infected. Chronic infection depends on an immune evasion mechanism termed antigenic variation, which in turn relies on monoallelic expression of 1 of ~60 var genes. Understanding antigenic variation and the transcriptional regulation of monoallelic expression is important for developing drugs and/or vaccines. The var gene family encodes the antigenic surface proteins that decorate infected erythrocytes. Until recently, studying the underlying genetic elements that regulate monoallelic expression in P. falciparum was difficult, and most studies relied on artificial systems such as episomal reporter genes. Our study was the first to use CRISPR/Cas9 genome editing for the functional study of an important, conserved genetic element of var genes—the intron—in an endogenous, episome-free manner. Our findings shed light on the role of the var gene intron in transcriptional regulation of monoallelic expression. IMPORTANCE Plasmodium falciparum is the most virulent species of malaria parasite, causing high rates of morbidity and mortality in those infected. Chronic infection depends on an immune evasion mechanism termed antigenic variation, which in turn relies on monoallelic expression of 1 of ~60 var genes. Understanding antigenic variation and the transcriptional regulation of monoallelic expression is important for developing drugs and/or vaccines. The var gene family encodes the antigenic surface proteins that decorate infected erythrocytes. Until recently, studying the underlying genetic elements that regulate monoallelic expression in P. falciparum was difficult, and most studies relied on artificial systems such as episomal reporter genes. Our study was the first to use CRISPR/Cas9 genome editing for the functional study of an important, conserved genetic element of var genes—the intron—in an endogenous, episome-free manner. Our findings shed light on the role of the var gene intron in transcriptional regulation of monoallelic expression.

scholarly journals Expression of var genes located within polymorphic subtelomeric domains of Plasmodium falciparum chromosomes.

1997 ◽  
Vol 17 (7) ◽  
pp. 3679-3686 ◽  
Author(s):  
K Fischer ◽  
P Horrocks ◽  
M Preuss ◽  
J Wiesner ◽  
S Wünsch ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Yeast Artificial Chromosome ◽  
Antigenic Variation ◽  
Chromosome Analysis ◽  
Artificial Chromosome ◽  
Chromosome 8 ◽  
Chromosome 2 ◽  
Var Genes ◽  
Var Gene ◽  
Contig Map

Plasmodium falciparum var genes encode a diverse family of proteins, located on the surfaces of infected erythrocytes, which are implicated in the pathology of human malaria through antigenic variation and adhesion of infected erythrocytes to the microvasculature. We have constructed a complete representative telomere-to-telomere yeast artificial chromosome (YAC) contig map of the P. falciparum chromosome 8 for studies on the chromosomal organization, distribution, and expression of var genes. Three var gene loci were identified on chromosome 8, two of which map close to the telomeres at either end of the chromosome. Analysis of the previously described chromosome 2 contig map and random P. falciparum telomeric YAC clones revealed that most, if not all, 14 P. falciparum chromosomes contain var genes in a subtelomeric location. Mapping the chromosomal location of var genes expressed in a long-term culture of the P. falciparum isolate Dd2 revealed that four of the five different expressed var genes identified map within subtelomeric locations. Expression of var genes from a chromosomal domain known for frequent rearrangements has important implications for the mechanism of var gene switching and the generation of novel antigenic and adhesive phenotypes.

scholarly journals The C-Terminal Segment of the Cysteine-Rich Interdomain of Plasmodium falciparum Erythrocyte Membrane Protein 1 Determines CD36 Binding and Elicits Antibodies That Inhibit Adhesion of Parasite-Infected Erythrocytes

2008 ◽  
Vol 76 (5) ◽  
pp. 1837-1847 ◽  
Author(s):  
Min Mo ◽  
Hooi Chen Lee ◽  
Masayo Kotaka ◽  
Makhtar Niang ◽  
Xiaohong Gao ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Membrane Protein ◽  
Erythrocyte Membrane ◽  
Malaria Vaccine ◽  
Antigenic Variation ◽  
Binding Specificity ◽  
Terminal Segment ◽  
Erythrocyte Membrane Protein ◽  
Falciparum Erythrocyte Membrane Protein ◽  
Parasite Strains

ABSTRACT Attachment of erythrocytes infected by Plasmodium falciparum to receptors of the microvasculature is a major contributor to the pathology and morbidity associated with malaria. Adhesion is mediated by the P. falciparum erythrocyte membrane protein 1 (PfEMP-1), which is expressed at the surface of infected erythrocytes and is linked to both antigenic variation and cytoadherence. PfEMP-1 contains multiple adhesive modules, including the Duffy binding-like domain and the cysteine-rich interdomain region (CIDR). The interaction between CIDRα and CD36 promotes stable adherence of parasitized erythrocytes to endothelial cells. Here we show that a segment within the C-terminal region of CIDRα determines CD36 binding specificity. Antibodies raised against this segment can specifically block the adhesion to CD36 of erythrocytes infected with various parasite strains. Thus, small regions of PfEMP-1 that determine binding specificity could form suitable components of an antisequestration malaria vaccine effective against different parasite strains.

scholarly journals Plasmodium falciparum Associated with Severe Childhood Malaria Preferentially Expresses PfEMP1 Encoded by Group A var Genes

2004 ◽  
Vol 199 (9) ◽  
pp. 1179-1190 ◽  
Author(s):  
Anja T.R. Jensen ◽  
Pamela Magistrado ◽  
Sarah Sharp ◽  
Louise Joergensen ◽  
Thomas Lavstsen ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Falciparum Malaria ◽  
Antigenic Variation ◽  
Severe Disease ◽  
Asymptomatic Infection ◽  
Var Genes ◽  
Life Threatening ◽  
Group A ◽  
Var Gene

Parasite-encoded variant surface antigens (VSAs) like the var gene–encoded Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) family are responsible for antigenic variation and infected red blood cell (RBC) cytoadhesion in P. falciparum malaria. Parasites causing severe malaria in nonimmune patients tend to express a restricted subset of VSA (VSASM) that differs from VSA associated with uncomplicated malaria and asymptomatic infection (VSAUM). We compared var gene transcription in unselected P. falciparum clone 3D7 expressing VSAUM to in vitro–selected sublines expressing VSASM to identify PfEMP1 responsible for the VSASM phenotype. Expression of VSASM was accompanied by up-regulation of Group A var genes. The most prominently up-regulated Group A gene (PFD1235w/MAL7P1.1) was translated into a protein expressed on the infected RBC surface. The proteins encoded by Group A var genes, such as PFD1235w/MAL7P1.1, appear to be involved in the pathogenesis of severe disease and are thus attractive candidates for a vaccine against life-threatening P. falciparum malaria.

scholarly journals Population structuring of multi-copy, antigen-encoding genes in Plasmodium falciparum

eLife ◽  
2012 ◽  
Vol 1 ◽  
Author(s):  
Yael Artzy-Randrup ◽  
Mary M Rorick ◽  
Karen Day ◽  
Donald Chen ◽  
Andrew P Dobson ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Antigenic Variation ◽  
Agent Based ◽  
Var Genes ◽  
Sexual Recombination ◽  
Population Structuring ◽  
Cross Immunity ◽  
Pathogen Populations ◽  
Encoding Genes ◽  
Var Gene

The coexistence of multiple independently circulating strains in pathogen populations that undergo sexual recombination is a central question of epidemiology with profound implications for control. An agent-based model is developed that extends earlier ‘strain theory’ by addressing the var gene family of Plasmodium falciparum. The model explicitly considers the extensive diversity of multi-copy genes that undergo antigenic variation via sequential, mutually exclusive expression. It tracks the dynamics of all unique var repertoires in a population of hosts, and shows that even under high levels of sexual recombination, strain competition mediated through cross-immunity structures the parasite population into a subset of coexisting dominant repertoires of var genes whose degree of antigenic overlap depends on transmission intensity. Empirical comparison of patterns of genetic variation at antigenic and neutral sites supports this role for immune selection in structuring parasite diversity.

scholarly journals Differential, Positional-Dependent Transcriptional Response of Antigenic Variation (var) Genes to Biological Stress in Plasmodium falciparum

PLoS ONE ◽  
2009 ◽  
Vol 4 (9) ◽  
pp. e6991 ◽  
Author(s):  
Elli Rosenberg ◽  
Amir Ben-Shmuel ◽  
Oshrit Shalev ◽  
Rosa Sinay ◽  
Alan Cowman ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Antigenic Variation ◽  
Transcriptional Response ◽  
Var Genes ◽  
Biological Stress

scholarly journals Antigenic variation in malaria: in situ switching, relaxed and mutually exclusive transcription of var genes during intra-erythrocytic development in Plasmodium falciparum

1998 ◽  
Vol 17 (18) ◽  
pp. 5418-5426 ◽  
Author(s):  
A. Scherf ◽  
R. Hernandez-Rivas ◽  
P. Buffet ◽  
E. Bottius ◽  
C. Benatar ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Antigenic Variation ◽  
Var Genes

scholarly journals Interactions between Merozoite Surface Proteins 1, 6, and 7 of the Malaria Parasite Plasmodium falciparum

2006 ◽  
Vol 281 (42) ◽  
pp. 31517-31527
Author(s):  
Christian W. Kauth ◽  
Ute Woehlbier ◽  
Michaela Kern ◽  
Zeleke Mekonnen ◽  
Rolf Lutz ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Malaria Parasite ◽  
Surface Proteins ◽  
Parasite Plasmodium ◽  
Parasite Plasmodium Falciparum

scholarly journals The large diverse gene family var encodes proteins involved in cytoadherence and antigenic variation of plasmodium falciparum-infected erythrocytes

Cell ◽  
1995 ◽  
Vol 82 (1) ◽  
pp. 89-100 ◽  
Author(s):  
Xin-zhuan Su ◽  
Virginia M. Heatwole ◽  
Samuel P. Wertheimer ◽  
Frangoise Guinet ◽  
Jacqueline A. Herrfeldt ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Gene Family ◽  
Antigenic Variation
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