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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 Transgenic parasites that are selected to express a  var  gene in which the PfEMP1 coding region has been replaced by a drug-selectable marker silence all other  var  genes in the genome, thus effectively knocking out all PfEMP1 expression and indicating that the modified gene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.

Mutually Exclusive Expression of Virulence Genes by Malaria Parasites Is Regulated Independently of Antigen Production