A coordinated transcriptional switching network mediates antigenic variation of human malaria parasites

A key attribute that enables malaria parasites to avoid immune clearance is their ability to systematically alter their exposed antigens through the tightly regulated transcriptional control of individual members of a large, multicopy gene family called var. Expression of these genes is mutually exclusive and controlled epigenetically, with switching requiring coordinated var gene activation and silencing. Here we provide the first molecular evidence for a transcriptional network anchored by a universally conserved gene called var2csa that coordinates the switching process. We also provide evidence for a structured switching bias that shifts overtime and could shape the pattern of var expression over the course of a lengthy infection. Our results add an additional layer to the epigenetic mechanisms previously implicated in regulating var gene transcription. These results also provide an explanation for how parasites possessing a relatively small repertoire of variant antigen encoding genes can coordinate switching events to limit antigen exposure, thereby maintaining chronic infections.