Biomedical subjects

Kirk W Deitsch

Publications and source records attributed to Kirk W Deitsch.

7 recordsLinked to original sources

PubMed2007

Epigenetic memory at malaria virulence genes.

During its red blood cell stage, the malaria parasite Plasmodium falciparum can switch its variant surface proteins (P. falciparum erythrocyte membrane protein 1) to evade the host immune response. The var gene family encodes P. falciparum erythrocyte membrane protein 1, different versions of which have unique binding specificities to various human endothelial surface molecules. Individual parasites each contain approximately 60 var genes at various locations within their chromosomes; however, parasite isolates contain different complements of var genes, thus, the gene family is enormous with a virtually unlimited number of members. A single var gene is expressed by each parasite in a mutually exclusive manner. We report that control of var gene transcription and antigenic variation is associated with a chromatin memory that includes methylation of histone H3 at lysine K9 as an epigenetic mark. We also discuss how gene transcription memory may affect the mechanism of pathogenesis and immune evasion.

Animals↗

PubMed2005

Malaria virulence genes controlling expression through chromatin modification.

Mutually exclusive expression within the var gene family of the malaria parasite Plasmodium falciparum is important for parasite survival and virulence. In this issue of Cell, Duraisingh et al. and Freitas-Junior et al. provide evidence for the role of Sir2-dependent alterations in chromatin structure and changes in subnuclear chromatin localization in regulating var gene expression (Duraisingh et al., 2005; Freitas-Junior et al., 2005).

Animals↗

PubMed2005

Targeting malaria parasite proteins to the erythrocyte.

The intraerythrocytic stages of the protozoan parasite Plasmodium falciparum reside within a parasitophorous vacuole (PV) and set up unique "extraparasite, intraerythrocyte" protein-trafficking pathways that target parasite-encoded proteins to the erythrocyte cytoplasm and cell surface. Two recent articles report the identification of trafficking motifs that regulate the transport of parasite-encoded proteins across the PV. These articles greatly aid the annotation of the parasite "secretome" catalog of proteins that are targeted to the erythrocyte cytoplasm or cell membrane.

Amino Acid Sequence↗

PubMed2005

A silenced Plasmodium falciparum var promoter can be activated in vivo through spontaneous deletion of a silencing element in the intron.

Introns of Plasmodium falciparum var genes act as transcriptional silencing elements that help control antigenic variations. In transfected episomes, intron silencing of a drug-selectable marker under var promoter control is reversed by the spontaneous deletion of key intron regions. The resulting promoter activation does not affect the transcription of chromosomal var genes.

Animals↗

PubMed2004

Pregnancy-associated malaria and the prospects for syndrome-specific antimalaria vaccines.

Aided by the Plasmodium falciparum genome project, recent discoveries regarding the molecular basis of malaria pathogenesis have led to a better understanding of the interactions between host and parasite. Although vaccines that prevent infection by malaria parasites remain only hopes for the future, there are now more immediate prospects for vaccines that protect against specific disease syndromes. Here, we discuss the latest advances in the development of a vaccine that specifically targets pregnancy-associated malaria (PAM).

Animals↗

PubMed2004

Variant surface antigens, virulence genes and the pathogenesis of malaria.

The first Molecular Approaches to Malaria meeting was held 2-5 February 2000 in Lorne, Australia. Following the meeting, Brian Cooke, Mats Wahlgren and Ross Coppel predicted that research into the molecular details of the mechanisms behind sequestration of parasitized erythrocytes would "become increasingly more complicated, with further interactions, receptors, ligands and functional domains". Furthermore, they cautioned that "the challenge will be not to lose ourselves in the molecular detail, but remain focused on the role of [the var genes and other multigene families] in pathogenesis of malaria". We contemplate on these statements, following the recent second Molecular Approaches to Malaria meeting, which was held at the same venue on 2-5 February 2004.

Animals↗

PubMed2003

Plasmodium falciparum var genes are regulated by two regions with separate promoters, one upstream of the coding region and a second within the intron.

Antigenic variation in Plasmodium falciparum malaria parasites results from switches in expression among members of the multicopy var gene family. This family is subject to allelic exclusion by which particular genes are expressed while the rest of the family remains transcriptionally silent. Evidence from reporter constructs indicates that var gene silencing involves a cooperative interaction between the var intron and an upstream element and requires transition of the parasites through S-phase of the cell cycle. These findings implicate chromatin assembly in the process of regulating var gene expression and antigenic variation. Here we characterize the var intron and the elements within it that are necessary for var transcriptional silencing. Alignments of var introns show a highly conserved structure that consists of three discreet regions with distinct base pair compositions. The middle region is highly AT-rich and is sufficient to silence an associated var promoter. Constructs that include a typical var intron upstream of a reporter gene or drug-selectable marker reveal that the intron also possesses promoter activity, presumably providing an explanation for the origin of the previously described var "sterile" transcripts. Deletions that disable the promoter activity of the intron also eliminate its ability to function as a silencer. These findings suggest that interactions between the regions of these two promoters and the generation of the sterile transcripts play a significant role in regulating var gene expression.

Alleles↗