The antigenic switching network of Plasmodium falciparum and its implications for the immuno-epidemiology of malaria

Antigenic variation in the human malaria parasite Plasmodium falciparum involves sequential and mutually exclusive expression of members of the var multi-gene family and appears to follow a non-random pattern. In this study, using a detailed in vitro gene transcription analysis of the culture-adapted HB3 strain of P. falciparum , we show that antigenic switching is governed by a global activation hierarchy favouring short and highly diverse genes in central chromosomal location. Longer and more conserved genes, which have previously been associated with severe infection in immunologically naive hosts, are rarely activated, however, implying an in vivo fitness advantage possibly through adhesion-dependent survival rates. We further show that a gene’s activation rate is positively associated sequence diversity, which could offer important new insights into the evolution and maintenance of antigenic diversity in P. falciparum malaria. DOI: http://dx.doi.org/10.7554/eLife.01074.001 eLife digest Our ability to acquire immunity to a disease depends on our immune system learning to recognise foreign molecules—called antigens—that are specific to the disease-causing virus, bacterium or parasite. However, some pathogens, such as the malaria-causing parasite Plasmodium falciparum , get around this defence through a process called antigenic variation. This involves the parasite switching between different antigens over the course of an infection, preventing the host immune system from learning to recognise them and leading to infections that last many weeks or even months. The main antigen in P. falciparum is a protein called PfEMP1, which is encoded by a family of genes called var (‘variable’). Var genes have evolved to be highly diverse, and different parasites have different repertoires of around 50–60 var genes. This ensures that there are a huge number of distinct variants of the PfEMP1 antigen available within the population, allowing the malaria parasite to maintain long-lasting infections and also to infect the same individuals again and again. Previous work has shown that the expression of var genes is not random, but it is not clear what determines which genes are expressed at any given time. Now, Noble et al. have performed a detailed investigation of antigenic switching in P. falciparum . Using clonal parasites, they closely monitored the expression of the entire var gene repertoire during many generations of parasite culture. They observed that although different cultures initially expressed distinct var genes, most of them ended up expressing two particular genes— var27 and var29 —at high levels, indicating a hard-wired gene ‘activation hierarchy’. Noble et al. found that whenever the parasites switched antigens, var genes that were centrally located on chromosomes—such as var27 and var29 —were more likely to be activated than those at the ends of chromosomes. Moreover, var genes that were highly diverse were more likely to be activated than more conserved genes: this is the first evidence linking var gene evolution with gene activation probabilities. Together, these factors gave rise to the proposed activation hierarchy, which favours genes optimised for immune evasion and aids their continued evolution and diversification. Further work is now needed to identify the molecular mechanisms that control antigenic switching and to determine whether these could represent new therapeutic targets for malaria. DOI: http://dx.doi.org/10.7554/eLife.01074.002