Toll-like receptors: cellular signal transducers for exogenous molecular patterns causing immune responses

Innate immunity initiates protection of the host organism against invasion and subsequent multiplication of microbes by specific recognition. Germ lin e-encoded receptors have been identified for microbial products such as man nan, lipopeptide, peptidoglycan (PGN), lipoteichoic acid (LTA), lipopolysac charide (LPS), and CpG-DNA. The Drosophila Toll protein has been shown to b e involved in innate immune response of the adult fruitfly. Members of the family of Toll-like receptors (TLRs) in vertebrates have been implicated as pattern recognition receptors (PRRs). Ten TLRs are known and six of these have been demonstrated to mediate cellular activation by distinct microbial products. TLR4 has been implicated as activator of adaptive immunity, and analysis of systemic LPS responses in mice led to the identification of LPS -resistant strains instrumental in its identification as a transmembrane LP S signal transducer. Structural similarities between TLRs and receptor mole cules involved in immune responses such as CD14 and the IL-1 receptors (IL- 1Rs), as well as functional analysis qualified TLR2 as candidate receptor f or LPS and other microbial products. Targeted disruption of the TLR9 gene i n mice led to identification of TLR9 as CpG-DNA signal transducer. Involvem ent of TLR5 in cell activation by bacterial flagellin has been demonstrated . Further understanding of recognition and cellular signaling activated thr ough the ancient host defense system represented by Toll will eventually le ad to means for its therapeutic modulation.