title: A Unique Virulence Gene Occupies a Principal Position in Immune Evasion by the Malaria Parasite Plasmodium falciparum.
abstract: Mutually exclusive gene expression, whereby only one member of a multi-gene family is selected for activation, is used by the malaria parasite Plasmodium falciparum to escape the human immune system and perpetuate long-term, chronic infections. A family of genes called var encodes the chief antigenic and virulence determinant of P. falciparum malaria. var genes are transcribed in a mutually exclusive manner, with switching between active genes resulting in antigenic variation. While recent work has shed considerable light on the epigenetic basis for var gene activation and silencing, how switching is controlled remains a mystery. In particular, switching seems not to be random, but instead appears to be coordinated to result in timely activation of individual genes leading to sequential waves of antigenically distinct parasite populations. The molecular basis for this apparent coordination is unknown. Here we show that var2csa, an unusual and highly conserved var gene, occupies a unique position within the var gene switching hierarchy. Induction of switching through the destabilization of var specific chromatin using both genetic and chemical methods repeatedly led to the rapid and exclusive activation of var2csa. Additional experiments demonstrated that these represent "true" switching events and not simply de-silencing of the var2csa promoter, and that activation is limited to the unique locus on chromosome 12. Combined with translational repression of var2csa transcripts, frequent "default" switching to this locus and detection of var2csa untranslated transcripts in non-pregnant individuals, these data suggest that var2csa could play a central role in coordinating switching, fulfilling a prediction made by mathematical models derived from population switching patterns. These studies provide the first insights into the mechanisms by which var gene switching is coordinated as well as an example of how a pharmacological agent can disrupt antigenic variation in Plasmodium falciparum.
authors.affiliation: Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, New York, United States of America.
authors.forename: Uchechi E
authors.initials: UE
authors.lastname: Ukaegbu
authors.affiliation: Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, New York, United States of America; Key Laboratory of Zoonosis, College of Veterinary Medicine, Jilin University, Xi An Da Lu, Changchun, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, New York, United States of America.
authors.forename: Adina R
authors.initials: AR
authors.lastname: Heinberg
authors.affiliation: University of Sciences Techniques and Technologies of Bamako, Bamako, Mali.
authors.forename: Mamadou
authors.initials: M
authors.lastname: Wele
authors.affiliation: Key Laboratory of Zoonosis, College of Veterinary Medicine, Jilin University, Xi An Da Lu, Changchun, China.
authors.forename: Qijun
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, New York, United States of America.
authors.forename: Kirk W
authors.initials: KW
authors.lastname: Deitsch
mesh_terms: D000940:Antigenic Variation; D000953:Antigens, Protozoan / Q000235:genetics / Q000378:metabolism*; D001381:Azepines / Q000494:pharmacology; D002738:Chloroquine / Q000494:pharmacology; D005786:Gene Expression Regulation; D056426:Genetic Loci; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D057131:Immune Evasion; D020128:Inhibitory Concentration 50; D016778:Malaria, Falciparum / Q000469:parasitology; D008962:Models, Theoretical; D010879:Piperazines / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D011401:Promoter Regions, Genetic; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology; D012319:RNA Polymerase II / Q000235:genetics / Q000378:metabolism; D013729:Terpenes / Q000494:pharmacology; D015533:Transcriptional Activation; D059467:Transcriptome
chemical_list: C551961:7-(2-(2-(dimethylamino)ethoxy)ethoxy)-6-methoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-(1-methylpiperidin-4-yl)quinazolin-4-amine; D000953:Antigens, Protozoan; D001381:Azepines; C518299:BIX 01294; D006877:Hydroxamic Acids; D010879:Piperazines; D015800:Protozoan Proteins; D011799:Quinazolines; D013729:Terpenes; C512601:VAR2CSA protein, Plasmodium falciparum; C085731:erythrocyte membrane protein 1, Plasmodium falciparum; C002511:chaetocin; C012589:trichostatin A; D002738:Chloroquine; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D012319:RNA Polymerase II; C054597:garcinol