Year: 2008
Type: article
Abstract: The general sensing apparatus used by the mammalian innate immune system was first revealed by a classical mutation, affecting the so-called Lps locus of mice. Positional cloning disclosed that Lps mutants, which were unable to sense bacterial lipopolysaccharides (LPS), had defects in Toll-like receptor 4, which thus emerged as the key transducing component of the LPS receptor. It is now known that awareness of microbes depends upon a small collection of germline-encoded receptors that are rather flexible in their recognition specificity and collectively discriminate between self and non-self. Mammals depend upon the TLRs to such an extent that mice lacking TLRs are quickly overwhelmed by a wide variety of infections. We have applied a classical genetic approach (mutagenesis and positional cloning) to analyze innate immunity in mice. Among the phenomena probed are Toll-like receptor signal transduction and resistance to infection by mouse cytomegalovirus (MCMV), a herpesvirus that has unusually sharp dose-lethality characteristics in the host species. Where TLR signaling is concerned, total of 22 mutations affecting 18 genes have been identified by screening approximately 30,000 mice. These mutations delineate much of what we know about how the mouse becomes aware of infection and begins to mount a response. With regard to the MCMV resistance screen, 46 phenovariants have been collected from among 22,000 mice screened to date. These affect genes in five functional categories, classed as ‘sensing’, signaling’, ‘effector’, ‘homeostatic’, and ‘developmental’. Through positional cloning, we have identified approximately half of these mutations. We estimate that a minimum of 300 genes and perhaps more than 1000 genes make non-redundant contributions to defense against MCMV. We hope to identify all of these genes and determine how they operate together to protect the host.
Author: B. Beutler
Institution: Scripps Research Institute
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,900
OpenAlex ID: W2024539554