The evolution of the Toll-like receptor system

Toll-like receptors are considered key elements of the immune system. The receptors scan the environment for danger signals that are mainly microbial and initiate a signaling cascade that mobilizes the appropriate host defense. Since the discovery of the protein Toll of the Drosophila melanogaster fruit fly, numerous (mostly putative) TLR genes have been identified throughout the animal kingdom. TLRs are structurally highly related proteins that belong to a very ancient receptor family. The first prototypical TLR gene appeared approximately 600 million years ago in the eumetazoan ancestor. During evolution TLRs underwent both purifying and diversifying selection, probably in order to adapt to coevolving microbial danger signals. This review describes the current knowledge of the structure, function, phylogeny, and distribution of TLRs across the animal kingdom, and the selective microbial pressures that drive TLR adaptation and species-specific TLR function.