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

Abstract

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

Plasmodium falciparumpopulation genetic complexity influences transcriptional profile and immune recognition of highly related genotypic clusters

“…There is likely a balance between the two, which perhaps can change depending on the level of individual and population-based immunity. It is therefore conceivable that when the level of immunity in the individual and/or population is low, there may be less of an advantage for the parasite to switch to an alternative var quickly [45, 56, 57], and further expression of multiple vars, rather than a single var, may not be detrimental to survival [13, 20, 56]. Such a dynamic is similar to what we observe in Senegal where parasites with the same genetic barcode express strikingly similar var genes over many years.…”

Transcription of the var genes from a freshly-obtained field isolate of Plasmodium falciparum shows more variable switching patterns than long laboratory-adapted isolates

“…In particular, var21 was more active in all the four clones and it was clearly recognized by the mutually exclusive expression system as in clone 5H. Thus like var27 and var29 that were preferentially expressed in the laboratory strain HB3 [ 25 ], var21 is the gene preferred by isolate FCYN0906.…”

“…Switch rates have been estimated to be approximately 2% or less per generation in long-term in vitro cultures, but can reach 16% in hosts infected with the laboratory clone 3D7 [ 21 , 22 ]. Recent studies also showed that the switch on/off rate is associated with chromosomal position, with centrally located genes apparently more highly transcribed in vitro than those in sub-telomeric location [ 16 , 19 , 20 , 23 , 24 ], especially those that are short and highly diverse [ 25 ]. As a result of these intrinsic factors, the switching patterns of var genes are thought to be non-random.…”

“…In addition, it is impossible to compare the transcription of each var gene quantitatively. To resolve this problem, var gene specific primer sets are needed (such as those recently designed for 3D7 and HB3) [ 25 , 36 ]. It may be possible to place the specific primers in the hypervariable regions of the DBLα domains [ 37 ], while it is first necessary to obtain sequences of the var gene repertoire of the wild isolates [ 27 ].…”

Chromatin modifications associated with activation and repression of stevor multigene family of plasmodium falciparum during the trophozoite stage

“…In P. falciparum, antigenic variation involves differential control of multigene families giving rise to hypervariable surface antigens during the course of an infection Stockdale et al 2008;Noble et al 2013). Using this mechanism the host immune system is continually confronted with a changing population of epitopes, making it difficult or impossible for the host to control or eliminate the pathogen.…”