Medicine (Northwest Academic Centre) - Research Publications
Permanent URI for this collection
Search Results
1 - 5 of 5
-
ItemHeterochromatin silencing and locus repositioning linked to regulation of virulence genes in Plasmodium faiciparum(CELL PRESS, 2005-04-08)The malaria parasite Plasmodium falciparum undergoes antigenic variation to evade host immune responses through switching expression of variant surface proteins encoded by the var gene family. We demonstrate that both a subtelomeric transgene and var genes are subject to reversible gene silencing. Var gene silencing involves the SIR complex as gene disruption of PfSIR2 results in activation of this gene family. We also demonstrate that perinuclear gene activation involves chromatin alterations and repositioning into a location that may be permissive for transcription. Together, this implies that locus repositioning and heterochromatic silencing play important roles in the epigenetic regulation of virulence genes in P. falciparum.
-
ItemEvidence that Plasmodium falciparum chromosome end clusters are cross-linked by protein and are the sites of both virulence gene silencing and activation(WILEY, 2006-10)The malaria parasite Plasmodium falciparum undergoes antigenic variation through allelic exclusion and variant expression of surface proteins encoded by the var gene family. Regulation of var genes is under epigenetic control and involves reversible silencing and activation that requires the physical repositioning of a var locus into a transcriptionally permissive zone of the nuclear periphery. P. falciparum chromosome ends appear to aggregate into large perinuclear clusters which house both subtelomeric and chromosome central var genes. In this study we further define the composition of telomeric clusters using fluorescent in situ hybridization, and provide evidence that chromosome end clusters are formed by cross-linking protein. In addition, we demonstrate that a subtelomeric reporter gene and a var gene remain within clusters regardless of their transcriptional status. Our findings support a model whereby a highly localized structure dedicated to the activation of a single var gene can be housed within a gene dense chromosome end cluster that is otherwise transcriptionally silent.
-
Item
-
ItemTranscription of multiple var genes by individual, trophozoite-stage Plasmodium falciparum cells expressing a chondroitin sulphate A binding phenotype(WILEY, 2002-03)In this study, we detected multiple var gene transcripts within single, mature trophozoite-infected red blood cells (iRBCs) bound to chondroitin sulphate A (CSA). Several of the var detected had previously been demonstrated to encode Plasmodium falciparum erythrocyte membrane protein-1 (PfEMP-1) variants with domains that mediated iRBC adhesion to receptors other than CSA. Parasites expressing the CSA-adherent phenotype transcribed far more of one var than of all others, but this gene was different from the two other var previously purported to encode adhesion to CSA. Previous work suggesting that only single var are transcribed by mature trophozoites needs re-examination in the light of these data from single, infected cells.
-
ItemAnalysis of pfcrt, pfmdr1, dhfr, and DHPS mutations and drug sensitivities in Plasmodium falciparum isolates from patients in Vietnam before and after treatment with artemisinin(AMER SOC TROP MED & HYGIENE, 2003-03)We have analyzed artemisinin sensitivity in Plasmodium falciparum isolates obtained from patients in South Vietnam and show that artemisinin sensitivity does not differ before and after drug treatment. There was an increase in the level of mefloquine resistance in the isolates after drug treatment that was concomitant with a decrease in chloroquine resistance, suggesting that treatment with artemisinin has selected for increased mefloquine resistance. Mutations in the pfmdr1 gene, previously shown to be associated with sensitivity to mefloquine, were selected against. All isolates resistant to chloroquine encoded Thr-76 in the pfcrt gene consistent with an essential role in the mechanism of chloroquine resistance. Mutations in pfmdr1 also were linked to chloroquine resistance. High levels of mutation in dhfr and dhps genes, which have previously been associated with Fansidar resistance, also were found, suggesting that this drug would not be useful for malaria control in this part of Vietnam.