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

Annu Rev Immunol. 2006;24:353-89. 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.

Publication types

  • Review

MeSH terms

  • Animals
  • Ethylnitrosourea / toxicity
  • Humans
  • Immunity, Innate / genetics
  • Infections / genetics
  • Infections / 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


  • Mutagens
  • Toll-Like Receptors
  • Ethylnitrosourea