Malaria parasites avoid immune clearance through their ability to systematically alter antigens exposed on the surface of infected red blood cells. This is accomplished by tightly regulated transcriptional control of individual members of a large, multicopy gene family called var and is the key to both the virulence and chronic nature of malaria infections. Expression of var genes is mutually exclusive and controlled epigenetically, however how large populations of parasites coordinate var gene switching to avoid premature exposure of the antigenic repertoire is unknown. Here, we provide evidence for a transcriptional network anchored by a universally conserved gene called var2csa that coordinates the switching process. We describe a structured switching bias that shifts overtime and could shape the pattern of var expression over the course of a lengthy infection. Our results provide an explanation for a previously mysterious aspect of malaria infections and shed light on how parasites possessing a relatively small repertoire of variant antigen-encoding genes can coordinate switching events to limit antigen exposure, thereby maintaining chronic infections.
Keywords: P. falciparum; antigenic switching; gene expression; immune evasion; infectious disease; malaria pathogenesis; microbiology; mutually exclusive expression.
Malaria causes severe illness and deaths in hundreds of thousands of people each year. Most of them are young children in Sub-Saharan Africa. The disease is transmitted when a mosquito carrying single-celled Plasmodium parasites bites a human, introducing the parasites into the bloodstream, where they enter red blood cells. When a red blood cell becomes infected, the parasite presents a protein on the cell’s surface that the immune system can recognize to start fighting the infection. Immune cells then produce antibodies that flag infected cells for destruction, relieving the symptoms of the disease. To avoid being destroyed in this manner, the parasites repeatedly ‘change’ the protein that ends up on the surface of the red blood cells. With each change, the number of parasites rebounds, symptoms return, and the immune system must produce new antibodies. As the parasites and immune system battle it out, patients may experience repeated flare-ups of symptoms for well over a year. To change the protein that is presented on the surface of red blood cells, Plasmodium parasites switch the genes in the var gene family on and off one at a time. Each of these genes encodes a different surface protein, and the parasites may cycle through the entire var gene family during an infection. However, it remains a mystery how the millions of infecting parasites coordinate to produce the same surface protein each time. Zhang et al. show that a gene from Plasmodium parasites called var2csa is responsible for coordinating protein switching through a set pattern that allows the parasites to synchronize which protein they switch to next. Deleting the var2csa gene in malaria parasites blocks protein switching and disables this coordinated immune evasion tactic. Zhang et al.’s experiments provide new insights about protein switching in malaria parasites. Further research may help scientists characterize each step in the process and identify which steps can be targeted to treat malaria. While not a cure, treatments that disable protein switching could reduce the number of times patients relapse and relieve symptoms. More generally, the results of Zhang et al. describe a mechanism for coordinated gene expression that may be used in organisms other than Plasmodium, including humans.
© 2022, Zhang et al.