ABSTRACT
Toll-like receptors (TLRs) represent a primary line of defense against invading pathogens, including bacteria, viruses, fungi, and parasites.1,2 Recognition of conserved microbial components by these receptors triggers innate immune responses that result in inflammation, antiviral responses, and maturation of dendritic cells, and ultimately leads to the clearance of the infectious agents. TLRs contain extracellular domains with leucine-rich repeats for ligand binding and intracellular Toll/interleukin-1 receptor (TIR) domains for signaling. The ligand binding domain of a TLR recognizes various pathogen-associated molecules, including lipopeptide (ligand of TLR2), double-stranded RNA (TLR3), lipopolysaccharide (TLR4), flagellin (TLR5), single-stranded RNA (TLR7), and unmethylated CpG DNA (TLR9).3,4 The intracellular TIR domain interacts with TIR domains in adaptor molecules such as MyD88, TIRAP, TRIF, and TRAM to initiate pathogen-specific immune responses,5,6
All living organisms face the challenge of defending themselves against microorganisms in the environment. Although the adaptive immune system has been subject to considerable study, the contribution of the innate immune system to defense against microbial pathogens has been less well appreciated. Innate immunity is often regarded as relatively non-specific. However, recent studies have shown that the innate immune system has a much greater specificity than previously thought, and can indeed respond to specific antigens. The first step in innate immunity is the recognition of microorganisms by receptors that recognize specific molecules that are present in the pathogen but not in self tissues. In mammals, a family of Toll-like receptors (TLRs) plays a central role in this discrimination, and ten human TLRs have been identified to date (Figure 1.1).
