Biomedical subjects

Kirk Deitsch

Publications and source records attributed to Kirk Deitsch.

6 recordsLinked to original sources

PubMed2006

Variant antigen gene expression in malaria.

Pathogens of the genus Plasmodium are unicellular parasites that infect a variety of animals, including reptiles, birds and mammals. All Plasmodium species target host erythrocytes and replicate asexually within this niche. In humans, proliferation within erythrocytes causes disease symptoms ranging from asymtomatic infection to severe disease, including mild to severe febrile and respiratory symptoms, profound anaemia and obstruction of blood flow. The most serious form of human malaria is caused by Plasmodium falciparum, a pathogen that is responsible for several million deaths annually throughout the developing world. Malaria parasites succeed in evading the host immune response to establish long-term, persistent infections, thus increasing the efficiency by which they are transmitted to the mosquito vector. The ability to evade the host immune system, in particular the avoidance of antibody-mediated immunity against parasite-encoded surface proteins, is the result of amplification of extensive repertoires of multicopy, hypervariable gene families that encode infected erythrocyte or merozoite surface proteins. Via switching between antigenically diverse genes within these large families, populations of parasites have the capacity for rapid variation in antigenicity and virulence over the course of an infection. Here we review the amplification and generation of antigenic diversity within the Plasmodium variant gene families, as well as discuss the mechanisms underlying their tightly controlled gene expression and antigenic switching.

Animals↗

PubMed2006

Deciphering the export pathway of malaria surface proteins.

The intra-erythrocytic stages of Plasmodium falciparum assemble a unique protein trafficking system that targets parasite proteins to the red cell cytoplasm and cell surface. It is through this trafficking pathway that the primary virulence determinants of P. falciparum infections are targeted to the erythrocyte surface to mediate adhesion to host endothelial cells. A recent study has shown that SBP-1, a parasite protein associated with Maurer's clefts in the infected red cell cytosol, is essential for transport of the virulence factor PfEMP-1. This discovery sheds new light on the little-understood mechanisms that regulate protein trafficking in infected cells.

Animals↗

PubMed2006

Activation, silencing and mutually exclusive expression within the var gene family of Plasmodium falciparum.

The var gene family of the human malaria parasite Plasmodium falciparum remains a topic of intense research focus due to the key role these antigen-encoding genes play in the ability of parasites to cause disease and avoid the human immune response. In recent years, as molecular tools for investigating the mechanisms that coordinate var gene expression have become more sophisticated, numerous insights have been acquired into how parasites manage to regulate transcription of this large gene family such that only a single gene is expressed at a time. The results of different experimental approaches have implicated mechanisms of chromatin modification, subnuclear localisation, promoter/promoter interactions and sterile RNAs in the silencing and activation of individual var genes, however, the roles that each of these different aspects play remain ill defined. In addition, some conflicting data regarding silencing and monoallelic expression of recombinant var promoters have recently been published, thus adding to the difficulty of understanding this complex phenomenon. In this review, we hope to present some of the existing data regarding this controversial topic in a way that will be both informative and constructive in our efforts to understand the molecular aspects of antigenic variation by malaria parasites.

Animals↗

PubMed2006

Mutually exclusive expression of virulence genes by malaria parasites is regulated independently of antigen production.

The primary virulence determinant of Plasmodium falciparum malaria parasite-infected cells is a family of heterogeneous surface receptors collectively referred to as PfEMP1. These proteins are encoded by a large, polymorphic gene family called var. The family contains approximately 60 individual genes, which are subject to strict, mutually exclusive expression, with the single expressed var gene determining the antigenic, cytoadherent, and virulence phenotype of the infected cell. The mutually exclusive expression pattern of var genes is imperative for the parasite's ability to evade the host's immune response and is similar to the process of "allelic exclusion" described for mammalian Ig and odorant receptor genes. In mammalian systems, mutually exclusive expression is ensured by negative feedback inhibition mediated by production of a functional protein. To investigate how expression of the var gene family is regulated, we have created transgenic lines of parasites in which expression of individual var loci can be manipulated. Here we show that no such negative feedback system exists in P. falciparum and that this process is dependent solely on the transcriptional regulatory elements immediately adjacent to each gene. Transgenic parasites that are selected to express a var gene in which the PfEMP1 coding region has been replaced by a drug-selectable marker silence all other var genes in the genome, thus effectively knocking out all PfEMP1 expression and indicating that the modified gene is still recognized as a member of the var gene family. Mutually exclusive expression in P. falciparum is therefore regulated exclusively at the level of transcription, and a functional PfEMP1 protein is not necessary for viability or for proper gene regulation in cultured parasites.

Animals↗

PubMed2006

Strict pairing of var promoters and introns is required for var gene silencing in the malaria parasite Plasmodium falciparum.

The human malaria parasite, Plasmodium falciparum, maintains a persistent infection altering the proteins expressed on the surface of the infected red blood cells, thus avoiding the host immune response. The primary surface antigen, a protein called PfEMP1, is encoded by a multicopy gene family called var. Each individual parasite only expresses a single var gene at a time, maintaining all other members of the family in a transcriptionally silent state. Previous work using reporter genes in transiently transfected plasmid constructs implicated a conserved intron found in all var genes in the silencing process. Here we have utilized episomal recombination within stably transformed parasites to generate different var promoter and intron arrangements and show that loss of the intron results in var promoter activation. Further, in multicopy plasmid concatamers, each intron could only silence a single promoter, suggesting a one-to-one pairing requirement for silencing. Transcriptionally active, "unpaired" promoters remained active after integration into a chromosome; however, they were not recognized by the pathway that maintains mutually exclusive var gene expression. The data indicate that intron/promoter pairing is responsible for silencing each individual var gene and that disruption of silencing of one gene does not affect the transcriptional activity of neighboring var promoters. This suggests that silencing is regulated at the level of individual genes rather than by assembly of silent chromatin throughout a chromosomal region, thus providing a possible explanation of how a var gene can be maintained in a silent state while the immediately adjacent var gene is transcriptionally active.

Alleles↗

PubMed2006

Antigenic variation by protozoan parasites: insights from Babesia bovis.

Antigenic variation of surface membrane proteins by protozoan parasites enables these pathogenic organisms to avoid host immune responses and thus perpetuate long-term infections. Babesia bovis, the causative agent of severe babesiosis in cattle, was previously shown to undergo antigenic variation through modifications to its primary surface antigen, a protein called VESA1. In this issue, Al-Khedery and Allred provide a detailed description of the genes that encode VESA1 and present convincing evidence for progressive, segmental gene conversion in the generation of variant forms of this surface antigen.

Animals↗