Genetic analysis of host resistance: Toll-like receptor signaling and immunity at large.
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.
Department of Immunology, Scripps Research Institute, La Jolla, California 92037, USA. bruce@scripps.edu
Bruce
B
Beutler
Zhengfan
Z
Jiang
Philippe
P
Georgel
Karine
K
Crozat
Ben
B
Croker
Sophie
S
Rutschmann
Xin
X
Du
Kasper
K
Hoebe
D000818:Animals; D005038:Ethylnitrosourea / Q000633:toxicity; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D007239:Infections / Q000235:genetics / Q000276:immunology; D051379:Mice; D018448:Models, Immunological; D015394:Molecular Structure; D009153:Mutagens / Q000633:toxicity; D009154:Mutation; D010641:Phenotype; D017634:Self Tolerance / Q000235:genetics; D015398:Signal Transduction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D051193:Toll-Like Receptors / Q000737:chemistry / Q000235:genetics* / Q000276:immunology; D014777:Virus Diseases / Q000235:genetics / Q000276:immunology
D009153:Mutagens; D051193:Toll-Like Receptors; D005038:Ethylnitrosourea