Evolution of transcriptional control of antigenic variation and virulence in human and ape malaria parasites

Abstract

Background The most severe form of human malaria is caused by the protozoan parasite Plasmodium falciparum. This unicellular organism is a member of a subgenus of Plasmodium called the Laverania that infects apes, with P. falciparum being the only member that infects humans. The exceptional virulence of this species to humans can be largely attributed to a family of variant surface antigens placed by the parasites onto the surface of infected red blood cells that mediate adherence to the vascular endothelium. These proteins are encoded by a large, multicopy gene family called var, with each var gene encoding a different form of the protein. By changing which var gene is expressed, parasites avoid immune recognition, a process called antigenic variation that underlies the chronic nature of malaria infections. Results Here we show that the common ancestor of the branch of the Laverania lineage that includes the human parasite underwent a remarkable change in the organization and structure of elements linked to the complex transcriptional regulation displayed by the var gene family. Unlike the other members of the Laverania, the clade that gave rise to P. falciparum evolved distinct subsets of var genes distinguishable by different upstream transcriptional regulatory regions that have been associated with different expression profiles and virulence properties. In addition, two uniquely conserved var genes that have been proposed to play a role in coordinating transcriptional switching similarly arose uniquely within this clade. We hypothesize that these changes originated at a time of dramatic climatic change on the African continent that is predicted to have led to significant changes in transmission dynamics, thus selecting for patterns of antigenic variation that enabled lengthier, more chronic infections. Conclusions These observations suggest that changes in transmission dynamics selected for significant alterations in the transcriptional regulatory mechanisms that mediate antigenic variation in the parasite lineage that includes P. falciparum. These changes likely underlie the chronic nature of these infections as well as their exceptional virulence.

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

“…With respect to the SMS model, var2csa displays the properties of a sink node, and is by far the most likely var gene to become highly activated in our cultures ( Figure 3A ). This gene also displays several other properties that make it an atypical member of the family, including universal conservation extending to related species that infect chimpanzees and gorillas ( Zilversmit et al, 2013 ; Gross et al, 2021 ) and the presence of a unique upstream regulatory region that includes an upstream open reading frame (uORF) resulting in translational repression of the mRNA ( Amulic et al, 2009 ; Bancells and Deitsch, 2013 ; Chan et al, 2017 ). The gene can therefore transcribe mRNA without producing PfEMP1 and thus could be transcriptionally activated repeatedly over the course of an infection without generating an antibody response by the host.…”

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

“…The location of a large proportion of the var gene family within subtelomeric regions makes them uniquely subject to frequent recombination and deletion events, an inherent plasticity that is reflected in the variable number of var genes observed in the genomes of different parasites isolates (55). Interestingly, despite the hyper-recombinogenic nature of the subtelomeric region in which it resides, var2csa remains conserved in all P. falciparum lines examined, and this conservation extends to the related species P. reichenowi and P. praefalciparum (35). We hypothesize that its role in mediating expression switching selects for its preservation within the genomes of wildtypes parasites.…”

“…With respect to the SMS model, var2csa displays the properties of a sink node, and is by far the most likely var gene to become highly activated in our cultures (Figure 3A). This gene also displays several other properties that make it an atypical member of the family, including universal conservation extending to related species that infect chimpanzees and gorillas (34,35) and the presence of a unique upstream regulatory region that includes an upstream open reading frame (uORF) resulting in translational repression of the mRNA (36)(37)(38). The gene can therefore transcribe mRNA without producing PfEMP1 and thus could be transcriptionally activated repeatedly over the course of an infection without generating an antibody response by the host.…”

Shared Mechanisms for Mutually Exclusive Expression and Antigenic Variation by Protozoan Parasites

“…The majority of the var gene family is subject to frequent recombination, resulting in the gene family displaying tremendous sequence diversity when the repertoire of var genes from different isolates are compared. However, two genes, referred to as var1csa and var2csa , appear to be conserved in all P. falciparum isolates from around the world and are also found in the related Plasmodium species that infect chimpanzees and gorillas ( Otto et al, 2018b ; Gross et al, 2021 ). It has been suggested that these genes could serve an additional function as conserved regulatory elements for coordinating mutually exclusive expression ( Mok et al, 2008 ; Ukaegbu et al, 2015 ).…”

“…Using both FISH (Figueiredo et al, 2002;Duraisingh et al, 2005) and Hi-C (Ay et al, 2014), var genes in P. falciparum have been shown to cluster in specific nuclear compartments, with the active var gene being separated from the silent loci, but no specific genetic elements have been connected to this clustering. As previously mentioned, there are two var genes, var1csa and var2csa, that are uniquely conserved amongst all isolates of Plasmodium falciparum, and this conservation extends to related species that infect chimpanzees and gorillas (Gross et al, 2021). This is in stark contrast to the highly polymorphic sequences of all other var genes, leading to speculation that these two genes could play a role in organization of the family or by directly regulating transcription (Mok et al, 2008;Ukaegbu et al, 2015).…”