A number of examples of molecular mimicry by pathogens, emulating natural endogenous ligands of paired receptors for immune evasion, have been described in the literature. Such interactions are particularly common with the inhibitory members of receptor pairs, bolstering the hypothesis that activating partners are a later evolutionary response to this immune escape strategy.
The first described interaction between a paired receptor and a viral protein identified ILT-2 and ILR-4 (LILRB1 and LILRB2) as targets for herpes simplex virus UL18 protein, which resembles an MHC-I molecule. Variations in susceptibility to mouse cytomegalovirus infection due to differences in Ly49-family paired receptors among mouse strains are well-characterized, and are attributed to the structural resemblance between the viral protein m157 and MHC-I molecules. The pathogenic bacterium Escherichia coli K1 exposes surface polysialic acid molecules that serve as a molecular mimic for the native ligand of the inhibitory receptor Siglec-11, but induces an opposing response through interactions with the paired activating receptor Siglec-16, exemplifying the benefit of activating receptors as defense mechanisms against molecular mimicry by pathogens.
Paired receptors are also used as viral entry receptors by a number of viruses and occasionally as entry mechanisms for other pathogens. Sialylation is common among mammalian cell-surface proteins and a number of pathogens use sialic acid - either self-synthesized or obtained from the host cell - to evade host immunity, including by interacting with inhibitory siglec receptors.