Parasite epigenetics and immune evasion: lessons from budding yeast

Abstract

The remarkable ability of many parasites to evade host immunity is the key to their success and pervasiveness. The immune evasion is directly linked to the silencing of the members of extended families of genes that encode for major parasite antigens. At any time only one of these genes is active. Infrequent switches to other members of the gene family help the parasites elude the immune system and cause prolonged maladies. For most pathogens, the detailed mechanisms of gene silencing and switching are poorly understood. On the other hand, studies in the budding yeast Saccharomyces cerevisiae have revealed similar mechanisms of gene repression and switching and have provided significant insights into the molecular basis of these phenomena. This information is becoming increasingly relevant to the genetics of the parasites. Here we summarize recent advances in parasite epigenetics and emphasize the similarities between S. cerevisiae and pathogens such as Plasmodium, Trypanosoma, Candida, and Pneumocystis. We also outline current challenges in the control and the treatment of the diseases caused by these parasites and link them to epigenetics and the wealth of knowledge acquired from budding yeast.

Figure 1

Schematics of varying genes and major mechanisms of variation in Pneumocystis carinii, Trypanosoma brucei, Plasmodium falciparum, and Candida glabrata. (A) In P. carinii, one to three MSG gene arrays (frequently flanked by MSR or PRT genes) are positioned next to a variable number of subtelomeric repeats and the telomeres (depicted by >>>). These genes (black arrows) lack promoters. To be expressed, a single MSG (red arrow) is transferred by homologous recombination to a unique expression site that contains an upstream conserved sequence (UCS). (B) In T. brucei, over 1,000 VSG gene donor sequences (black arrows) are exchanged by homologous recombination to one of fifteen expression sites. The VSG genes at these sites (red arrows) are adjacent to the telomeres and flanked by multiple 70 bp repeats. Several expression site-associated genes (ESAGs, open arrows) are distal to the telomere. All these and VSG are expressed in the direction of the telomere by one promoter (angled arrow). Only one of the fifteen expression sites is active at a time. Infrequent epigenetic switches of this site confers allelic exclusion and antigenic variation. (C) In P. falciparum, 60 VAR genes are positioned in tandem close to the telomeres or at interchromosomal locations (not shown). VAR_A (red arrow) point towards the telomere, while VAR_B (white arrow) point away. Six telomere-associated repeat elements (TARE) and several 12-base SPE sites (bind P. falciparum SPE2 interacting protein 2, PfSIP2) are located between VAR genes and the telomere. RIF and STE genes are frequently found in the vicinity of VAR genes. Only one VAR gene is expressed at a time. Switches between expressed VAR genes confer allelic exclusion and antigenic variation. (D) In C. glabrata, EPA genes are organized in arrays and are the last protein encoding genes before the telomere. In the example shown in the figure, EPA3 and EPA2 are mostly silenced, while EPA1 is expressed. ESAG, expression site-associated gene; PfSIP2, P. falciparum SPE2 interacting protein 2.

Figure 2

Subtelomeric gene silencing in Saccharomyces cerevisiae. (A) Spreading of histone deacetylation away from the telomere. Rap1 proteins associate with the telomere repeats and recruit Sir2/Sir3/Sir4 proteins. Sir2p is an enzyme that deacetylates the histones in the adjacent nucleosome. More Sir2/Sir3/Sir4 proteins are recruited by the now deacetylated nucleosome (dark octamer) to eventually spread histone deacetylation to the next nucleosome (depicted by the curved arrow above the nucleosomes). Histone deacetylation and silent information regulator (SIR) proteins can spread several kilobases away from the telomeres. (B) Subtelomeric cis-elements in S. cerevisiae. Repetitive core X and Y’ elements contain dormant origins of DNA replication (ACS, it binds origin recognition complex, ORC), internal telomeric sequences (ITS, they bind Rap1 proteins), chromatin boundaries (depicted by B, and subtelomeric anti-silencing regions (STARs). (C) Chromatin boundaries restrict the spreading of histone deacetylation and prevent the silencing of telomere-distal genes (red arrows). (D)ITS and ACS are protosilencers, which extend the spreading of SIR proteins or confer telomere-dependent silencing of genes (white arrows) beyond an active subtelomeric gene (red arrow). A hypothetical STAR and a chromatin boundary contribute to the maintenance of the active gene. ORC, origin recognition complex; SIR, silent information regulator.