The human malaria parasitePlasmodium falciparumcan sense environmental changes and respond by antigenic switching

Abstract

The primary antigenic and virulence determinant of the human malaria parasite Plasmodium falciparum is a variant surface protein called PfEMP1. Different forms of PfEMP1 are encoded by a multicopy gene family called var , and switching between active genes enables the parasites to evade the antibody response of their human hosts. var gene switching is key for the maintenance of chronic infections; however, what controls switching is unknown, although it has been suggested to occur at a constant frequency with little or no environmental influence. var gene transcription is controlled epigenetically through the activity of histone methyltransferases (HMTs). Studies in model systems have shown that metabolism and epigenetic control of gene expression are linked through the availability of intracellular S-adenosylmethionine (SAM), the principal methyl donor in biological methylation modifications, which can fluctuate based on nutrient availability. To determine whether environmental conditions and changes in metabolism can influence var gene expression, P . falciparum was cultured in media with altered concentrations of nutrients involved in SAM metabolism. We found that conditions that influence lipid metabolism induce var gene switching, indicating that parasites can respond to changes in their environment by altering var gene expression patterns. Genetic modifications that directly modified expression of the enzymes that control SAM levels similarly led to profound changes in var gene expression, confirming that changes in SAM availability modulate var gene switching. These observations directly challenge the paradigm that antigenic variation in P. falciparum follows an intrinsic, programed switching rate, which operates independently of any external stimuli.

Transcriptional plasticity of virulence genes provides malaria parasites with greater adaptive capacity for avoiding host immunity

“…Both “multiple” cells and “null” cells were unexpected based on previous assumptions regarding mutually exclusive expression, so we chose to investigate these two states in more detail. In a previous study, we found that the availability of intracellular S-adenosylmethionine (SAM), the principal methyl donor for methylation modifications, can influence var expression (39). Genetic modifications to SAM synthetase (SAMS), the enzyme producing SAM from methionine, led to profound changes in var expression.…”

Chromatin structure andvar2csa– a tango in regulation ofvargene expression in the human malaria parasite,Plasmodium falciparum?

“…We have similarly proposed that competition between var promoters could play an important role in selecting which var gene is active as well as contributing to var gene switching [41, 14]. The var2csa promoter appears to be unique in its competitiveness compared to other var promoters [21, 42], and thus its presence in the genome could serve to maintain expression levels of other var promoters within a range that is conducive to periodic switching. Its loss therefore could upset this balance, leading to reduced switching and lower levels of the var “minor” transcripts associated with var promoter activity.…”

Immune gene expression changes more during a malaria transmission season than between consecutive seasons.

“…Additionally, the parasite response to changing immune pressure in an infected human during these short periods remains elusive. Previous work has characterized the immune gene expression changes 26 associated with high and low numbers of repeated clinical malaria episodes across an eight year period 27 , while changes in the expression of P. falciparum variant surface antigen, PfEMP1, have been linked to changes in immune status 28, 29 . Since the P. falciparum blood-stages are responsible for all clinical symptoms of malaria and since we have access to peripheral blood to examine the human immune response at this stage, studying host and parasite gene expression from infected blood can provide information on how peripheral malaria immunity develops over one transmission season, whether this immunity wanes during the dry season, and how the parasite responds to these changes.…”