Genetic analysis of host resistance: Toll-like receptor signaling and immunity at large

• Published in: Annual Review of Immunology 2006-01, Vol.24 (1), p.353-389
• Main Authors: Beutler, Bruce, Jiang, Zhengfan, Georgel, Philippe, Crozat, Karine, Croker, Ben, Rutschmann, Sophie, Du, Xin, Hoebe, Kasper
• Format: Article
• Language: English
• Subjects: Animals; Ethylnitrosourea - toxicity; Humans; Immunity, Innate - genetics; Infection - genetics; Infection - immunology; Mice; Models, Immunological; Molecular Structure; Mutagens - toxicity; Mutation; Phenotype; Self Tolerance - genetics; Signal Transduction; T-Lymphocytes, Cytotoxic - immunology; Toll-Like Receptors - chemistry; Toll-Like Receptors - genetics; Toll-Like Receptors - immunology; Virus Diseases - genetics; Virus Diseases - immunology
• ISSN: 0732-0582; 1545-3278; 1365-2567
• DOI: 10.1146/annurev.immunol.24.021605.090552

Classical genetic methods, driven by phenotype rather than hypotheses, generally permit the identification of all proteins that serve nonredundant functions in a defined biological process. Long before this goal is achieved, and sometimes at the very outset, genetics may cut to the heart of a biological puzzle. So it was in the field of mammalian innate immunity. The positional cloning of a spontaneous mutation that caused lipopolysaccharide resistance and susceptibility to Gram-negative infection led directly to the understanding that Toll-like receptors (TLRs) are essential sensors of microbial infection. Other mutations, induced by the random germ line mutagen ENU (N-ethyl-N-nitrosourea), have disclosed key molecules in the TLR signaling pathways and helped us to construct a reasonably sophisticated portrait of the afferent innate immune response. A still broader genetic screen--one that detects all mutations that compromise survival during infection--is permitting fresh insight into the number and types of proteins that mammals use to defend themselves against microbes.