The first line of defense against parasites, as with other pathogens, is the innate immune system, which is 'hardwired' (faithful to genomic sequence) and primed even in the absence of infection. It is characterized by families of molecules – serum proteins and intracellular and cell-surface receptors – known as pattern recognition receptors (PRRs) that recognize generic molecular structures associated with different groups of pathogens. Among other actions, these receptors mobilize macrophages and granulocytes, unleashing antimicrobial proteins and reactive metabolites. They also mobilize dendritic cells, which activate the lymphocytes of the adaptive immune system, inducing proliferation of T cells and antibody-producing B cells with variable receptors that specifically recognize the parasite.

The canonical pattern-recognition receptor of the innate immune system is the cell surface Toll-Like Receptor-4 (TLR-4), which binds to the cell wall lipopolysaccharide (LPS) of Gram-negative bacteria [4]. Detailed phylogenetic analysis of the TLR family indicates strong conservation of sequence and function [5], but there is significant fine-detail polymorphism across the TLR-related pathway within the human population, linked to differences in immune responsiveness to bacterial infection [4]. Why would such polymorphisms exist? It is most likely that they are maintained by variations in TLR ligands among pathogens. But while the function of the innate receptors is to activate immediate reactions to microbial infection, some eukaryotic parasites can negatively signal through the same receptors [6], suggesting a complex trade-off for the host, resulting in selection of both ligand-binding and signaling variants which would resist pathogen repression.

Innate immunity alone seldom eliminates successful parasites, but it inhibits growth while recruiting the antigen-specific T and B cells of the adaptive immune system to proliferate and differentiate into effector cells competent to attack the infection. It is therefore the evasion of adaptive immunity that is indispensable to parasite survival [7], and for rapidly proliferating protozoa an effective evasion strategy is antigenic variation, in which the expression of distinct surface molecules allows new variants to escape immune recognition, quickly replacing those killed by the adaptive immune system.