(Problem 15) Malaria, one of the most pervasive and destructive of all infectiou
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(Problem 15) Malaria, one of the most pervasive and destructive of all infectious diseases, is caused by Plasmodium parasites that are transmitted via mosquitos. Plasmodium parasites are able to evade the host immune system by constantly altering the expression of their var genes, which encode Plasmodium surface antigens (L. H. Freitas-Junior et al., 2005, Cell 121:25-36). Individual var genes are expressed when chromatin structure is disrupted by chemical changes in histone proteins. What type of chemical changes in the histone proteins might be responsible for these changes in gene expression?Explanation / Answer
The proteins responsible for the cytoadherent properties of infected red cells are encoded by a multicopy gene family called var. While each parasite contains approximately 60 var genes within its genome, only a single copy is expressed at any given time. Over the course of an infection, expression switches to alternate copies within the family, resulting in antigenic variation and a persistent infection. Recent work has implicated changes in the structure of the chromatin that surround individual var genes as being important for controlling the expression of this gene family.
Each individual var gene contains two important regulatory elements, one upstream of each gene along the chromosome and a second with an intron that exists within the coding region of each gene. These elements act in a cooperative fashion to silence expression of all but a single var gene at a time. This cooperative interaction is required not only for var gene silencing, but also for recognition of each var gene by the process that ensures that only a single var gene is expressed at a time. The modifications that are made to the proteins that provide a scaffold for the chromosome to wrap around within the parasite nucleus. Within the area of the var genes, these scaffold proteins, called histones, are modified in a very specific way when a var gene is active as opposed to when it is silent. These studies provide us with key insights into how the parasite regulates expression of this large gene family, and identify potential targets for intervening in aspects of infection that contribute to the severity of the disease.
The P. falciparum genome contains approximately 60 var genes, however, frequent recombinations, deletions, and gene conversions create an endless var repertoire for antigenic variation. The processes of mutually exclusive var gene expression, rapid switching of the expressed gene, and the ability to generate a virtually limitless collection of new var genes is thought to be responsible for the fact that complete immunity to malaria infection is difficult or impossible to achieve.
There are three transcription states for a var gene: active, inactive but capable of being activated, and highly silenced. The probability that a gene will be turned on or turned off is not associated with chromosomal position nor the type of promoter per se but rather on the intrinsic properties of each gene. The initial dominant transcript determines the switch direction while the ability to switch to particular variant types may depend on the antigenic switching history of the parasite. Furthermore, switch rates have been suggested to be intrinsic and constant for the same var gene but different for individual var genes.
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