Sequence variation and structural conservation allows development of novel function and immune evasion in parasite surface protein families

Abstract

Trypanosoma and Plasmodium species are unicellular, eukaryotic pathogens that have evolved the capacity to survive and proliferate within a human host, causing sleeping sickness and malaria, respectively. They have very different survival strategies. African trypanosomes divide in blood and extracellular spaces, whereas Plasmodium species invade and proliferate within host cells. Interaction with host macromolecules is central to establishment and maintenance of an infection by both parasites. Proteins that mediate these interactions are under selection pressure to bind host ligands without compromising immune avoidance strategies. In both parasites, the expansion of genes encoding a small number of protein folds has established large protein families. This has permitted both diversification to form novel ligand binding sites and variation in sequence that contributes to avoidance of immune recognition. In this review we consider two such parasite surface protein families, one from each species. In each case, known structures demonstrate how extensive sequence variation around a conserved molecular architecture provides an adaptable protein scaffold that the parasites can mobilise to mediate interactions with their hosts.

Surface protein components from entomopathogenic nematodes and their symbiotic bacteria: effects on immune responses of the greater wax moth, Galleria mellonella (Lepidoptera: Pyralidae)

“…This interaction can lead to different responses, such as lack of recognition (molecular disguise or mimicry) or active immune depression of the host . Both processes have been well described in Steinernema feltiae , and it has been demonstrated that the cuticle/epicuticle of this EPN, particularly its lipid moieties, actively interferes with both humoral and cellular responses of G. mellonella larvae …”

Towards an anti-disease malaria vaccine

“…Endothelial tethering is mediated by the P. falciparum erythrocyte membrane protein 1, PfEMP1, a large protein family with ∼60 members encoded in each genome [13,14]. Each PfEMP1 is formed from multiple copies of two parasite-specific domain types, the CIDR and DBL domains, which are most often spatially arranged in a linear array (Figure 1) [15]. Different individual domains are capable of interacting with specific human endothelial surface proteins, including endothelial protein C receptor, EPCR [16], intracellular adhesion molecule 1, ICAM-1 [17] and cluster of differentiation 36, CD36 [18].…”

DNA Recombination Strategies During Antigenic Variation in the African Trypanosome

“…Antigenic variation in T. brucei was discussed by P. Borst in the previous version of this book, Mobile DNA II (7), and therefore we will attempt in this chapter to update that report by reviewing the findings that have been published since then. For more detailed discussion of specific aspects of T. brucei antigenic variation, the reader is referred to several recent reviews (21)(22)(23)(24)(25)(26)(27).…”

“…In fact, VSG appears to function solely as an antigen and does not perform any important biochemical activity, meaning that it is remarkably free to vary in sequence, with different functional VSGs sharing as little as 20% primary sequence identity (36). Still, there are clearly some limitations to VSG structure because all VSGs identified to date share strong features of secondary structure (37), in particular long α helices, which presumably stand perpendicular to the plasma membrane and contribute to the intact coat's depth and density (26,38).…”

“…First, the substrates used in SGC are different from activation of intact VSGs, in that at least one "end" of the reaction must be engaged through sequence homology between recombining VSG open reading frames, rather than through flanking homology. Since sequence homology between any two VSGs is normally very limited (26,38), this raises questions about the nature, efficiency and substrate preferences of the recombination reaction; for instance, can FIGURE 3 Hierarchy of variant surface glycoprotein (VSG) gene switching by recombination during infections by Trypanosoma brucei. The graph depicts the log of the number of T. brucei cells in a cow up to 70 days after infection (day 0).…”