Toll-like receptors and their role in experimental models of microbial infection ST Qureshi 1 and R Medzhitov 1 1 Section of Immunobiology, Yale University School of Medicine, New Haven, CT 06510, USA Effective host defense against microbial infection depends upon prompt recognition of pathogens, activation of immediate containment measures, and ultimately the generation of a specific and definitive adaptive immune response. The innate immune system of the host is responsible for providing constant surveillance against infection; when confronted by pathogens it deploys a series of rapidly acting antimicrobial effectors while simultaneously instructing the adaptive immune system as to the nature and context of the infectious threat. Pathogen recognition and activation of innate immunity is mediated by members of the Toll-like receptor (TLR) family through detection of conserved microbial structures that are absent from the host. Experimental models of infection using TLR-deficient mice, as well as limited human studies, have clearly demonstrated the critical role of TLRs in host defense against most major groups of mammalian pathogens. Genes and Immunity (2003) 4, 87–94. doi:10.1038/sj.gene.6363937 Keywords: toll-like receptor; innate immunity; infection Introduction Multicellular eukaryotic hosts are constantly challenged by microorganisms that are ubiquitous in the environ- ment or present as colonizers, mainly of the epithelial surfaces. While this microbial presence may be beneficial under certain conditions, even a slight disruption of host–microbe homeostasis can have devastating and potentially fatal consequences. Survival of the host is therefore critically dependent on efficient mechanisms for containment of normal flora as well as rapid elimination of invading pathogens. Such defenses are present in many forms, including physical barriers (keratinized surfaces, tight epithelial junctions), nonspe- cific secretory products (gastric acid, bile, lysozyme), and immunologic defenses. The primary function of the immune system is to identify and eliminate infection, and this is achieved through two major elements; an adaptive component consisting of exquisitely specific T- and B-lymphocytes that undergo clonal selection and expansion upon presentation of a foreign antigen, as well as an innate component that is characterized by its rapid mobilization and activation of effector mechanisms upon microbial challenge. 1 Of the two complementary sub- divisions, the innate immune system has far more ancient evolutionary origins (being the only immune system of primitive multicellular organisms) and is transmitted via the germline without undergoing the somatic gene rearrangements that characterize antigen receptors of the adaptive immune system. Activation of innate immunity constitutes the first line of host defense against infection, and provides instructive signals to the adaptive immune system by alerting it to the abnormal presence as well as the context of a microbial invader. 2,3 The principal cellular components of the innate immune system include polymorphonuclear leukocytes (PMNs), tissue macrophages, dendritic cells (DCs), mast cells, and natural killer (NK) cells. These diverse lineages are all characterized by their ability to rapidly respond to infection or a breach of normal tissue architecture and to recognize and remove microbes and/or damaged host cells. DCs play an especially critical role in bridging innate to adaptive immunity through presentation of microbial breakdown products to T-lymphocytes in the context of the major histocompatibility complex (MHC), thereby initiating specific adaptive immune responses. A variety of effector mechanisms of the innate immune system have been extensively characterized, including exocytosis of neutrophil granule contents, phagolysoso- mal fusion in the host cell cytoplasm, and production of reactive oxygen species and nitrogen intermediates. Despite this detailed understanding, the mechanisms of pathogen recognition by cells of the innate immune system that precede the induction of such effectors have remained elusive. Recently, a major molecular mechan- ism for innate immune recognition of pathogens was established through identification of the mammalian Toll-like receptor (TLR) gene family. 4,5 TLRs are one subset of a diverse group of molecules referred to as pattern recognition receptors (PRRs). 1,3 Examples of previously identified PRRs include C-reactive protein, serum amyloid protein, and man- nan-binding protein (all secreted into extracellular compartments), the mannose receptor and scavenger receptor (expressed on the macrophage cell surface), and the intracellular double-stranded RNA-activated protein kinase PKR. A major function of PRRs is to mobilize host Received 16 July 2002; revised 19 July 2002; accepted 23 July 2002 Correspondence: Dr ST Qureshi, Yale University School of Medicine, LCI 105, 333 Cedar Street, New Haven, CT 06520-8057, USA. E-mail: salman.qureshi@yale.edu Genes and Immunity (2003) 4, 87–94 & 2003 Nature Publishing Group All rights reserved 1466-4879/03 $25.00 www.nature.com/gene