Rapid turnover of Plasmodium falciparum var gene transcripts and genotypes during natural non-symptomatic infections

The var genes of Plasmodium falciparum code for the antigenically variant erythrocyte membrane proteins 1 (PfEMP1), a major factor for cytoadherence and immune escape of the parasite. Herein, we analyzed the var gene transcript turnover in two ongoing, non-symptomatic infections at sequential time points during two weeks. The number of different circulating genomes was estimated by microsatellite analyses. In both infections, we observed a rapid turnover of plasmodial genotypes and var transcripts. The rapidly changing repertoire of var transcripts could have been caused either by swift elimination of circulating var-transcribing parasites stemming from different or identical genetic backgrounds, or by accelerated switching of var gene transcription itself.

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DETECTION SENSITIVITY AND QUANTITATION OF PLASMODIUM FALCIPARUM VAR GENE TRANSCRIPTS BY REAL-TIME RT-PCR IN COMPARISON WITH CONVENTIONAL RT-PCR

American Journal of Tropical Medicine and Hygiene ◽

10.4269/ajtmh.2006.75.212 ◽

2006 ◽

Vol 75 (2) ◽

pp. 212-218 ◽

Cited By ~ 10

Author(s):

MICHELLE L. GATTON ◽

ELIZABETH V. FOWLER ◽

KARRYN GRESTY ◽

QIN CHENG ◽

NANHUA CHEN ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Real Time ◽

Detection Sensitivity ◽

Rt Pcr ◽

Gene Transcripts ◽

Var Gene

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

Molecular and Cellular Biology ◽

10.1128/mcb.17.7.3679 ◽

1997 ◽

Vol 17 (7) ◽

pp. 3679-3686 ◽

Cited By ~ 46

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.

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Multiple var gene transcripts are expressed in Plasmodium falciparum infected erythrocytes selected for adhesion

Molecular and Biochemical Parasitology ◽

10.1016/s0166-6851(01)00266-3 ◽

2001 ◽

Vol 114 (2) ◽

pp. 227-237 ◽

Cited By ~ 44

Author(s):

R Noviyanti

Keyword(s):

Plasmodium Falciparum ◽

Gene Transcripts ◽

Var Gene

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

Journal of Experimental Medicine ◽

10.1084/jem.20040274 ◽

2004 ◽

Vol 199 (9) ◽

pp. 1179-1190 ◽

Cited By ~ 212

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.

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

eLife ◽

10.7554/elife.00093 ◽

2012 ◽

Vol 1 ◽

Cited By ~ 31

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.

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Erythrocyte membrane proteins involved in the immune response to Plasmodium falciparum and Plasmodium vivax infection

Parasitology Research ◽

10.1007/s00436-021-07135-6 ◽

2021 ◽

Vol 120 (5) ◽

pp. 1789-1797

Author(s):

Cristian Castro-Salguedo ◽

Darío Mendez-Cuadro ◽

Carlos Moneriz

Keyword(s):

Immune Response ◽

Plasmodium Falciparum ◽

Membrane Proteins ◽

Plasmodium Vivax ◽

Erythrocyte Membrane ◽

Vivax Infection ◽

Erythrocyte Membrane Proteins

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A distinct 5' flanking var gene region regulates Plasmodium falciparum variant erythrocyte surface antigen expression in placental malaria

Molecular Microbiology ◽

10.1046/j.1365-2958.2002.02999.x ◽

2002 ◽

Vol 45 (1) ◽

pp. 155-167 ◽

Cited By ~ 21

Author(s):

Aleida Vazquez-Macias ◽

Perla Martinez-Cruz ◽

Maria Cristina Castaneda-Patlan ◽

Christine Scheidig ◽

Jurg Gysin ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Surface Antigen ◽

Placental Malaria ◽

Antigen Expression ◽

Gene Region ◽

Erythrocyte Surface ◽

Surface Antigen Expression ◽

Var Gene

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The Plasmodium falciparum var gene switching rate, switching mechanism and patterns of parasite recrudescence described by mathematical modelling

Parasitology ◽

10.1017/s0031182001001160 ◽

2002 ◽

Vol 124 (3) ◽

pp. 225-235 ◽

Cited By ~ 43

Author(s):

S. PAGET-MCNICOL ◽

M. GATTON ◽

I. HASTINGS ◽

A. SAUL

Keyword(s):

Plasmodium Falciparum ◽

Chronic Infection ◽

Malaria Parasite ◽

Gene Repertoire ◽

Switching Rate ◽

Specific Immunity ◽

Parasite Survival ◽

Gene Switching ◽

Variant Antigen ◽

Var Gene

Recrudescing Plasmodium falciparum parasitaemia is attributed to the switching of PfEMP1, a variant antigen family encoded by the var gene repertoire, and the host's immune response. We have developed a mathematical model which incorporates var gene switching, and variant specific, non-variant specific and non-specific immunity. By conducting a sensitivity analysis of the model we have defined the parameter limits which produce chronic and recrudescing infections. We explore 3 switching mechanisms: ordered, random and uncoupled switching. We show that if var genes switch on and off independently at variable rates through the repertoire a chronic clinical infection is predicted. The fastest switching-on rate that produces a chronic infection is 0·03% per generation. The model predicts that non-variant specific immunity plays an important role in reducing disease severity. This work illustrates the complex relationship between the malaria parasite and its host and shows that var gene switching at rates substantially slower than 2% are essential for parasite survival.

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