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Forward Genetic Analysis of TLR Pathways

A Shared System for the Detection of Endotoxin and Viral Infection

  • Chapter
Book cover Toll and Toll-Like Receptors: An Immunologic Perspective

Part of the book series: Molecular Biology Intelligence Unit ((MBIU))

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Abstract

The mammalian Toll-like receptors (TLRs) were first recognized as innate immune sensors when it was discovered that TLR4 is the key component of the mammalian endotoxin (lipopolysaccharide; LPS) receptor. This determination was made when a spontaneous mouse mutation, Lps, was positionally cloned and found to reside with the Tlr4 locus. In all, we now know of the existence of eleven mouse TLRs and ten human TLRs, which collectively serve as the principal sensors of the innate immune system. Without them, small inocula of microorganisms would pose a major threat to the host, growing unchecked for a long period of time before they are recognized. These TLRs are served by a collection of at least five adapter proteins, each with homology to the TLRs themselves, permitting homotypic interaction to occur. Since a pure forward genetic approach led to the identification of the LPS receptor, ENU mutagenesis has been applied to the identification of other critical components of TLR signaling pathways. This approach has revealed that one of the adapter proteins, Lps2 (also known as Trif or Ticam-1) is required for normal responses to double-stranded RNA and LPS. It now appears that two and only two branches of the LPS sensing pathway exist downstream of TLR4 in macrophages: one dependent upon the joint function of the adapter proteins MyD88 and MAL/Tirap; the other dependent upon Lps2. Poly I:C sensing, on the other hand, has but one recognizable branch, leading to type I interferon induction. Lps2 is an indispensable component of this branch. Destructive mutations affecting Lps2 cause resistance to LPS toxicity, but also, heightened susceptibility to infection by mouse cytomegalovirus (mCMV). Lps2 is therefore the most proximal component of a signal integration system required for innate immune responses to both viral and bacterial infections.

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Authors and Affiliations

  1. Department of Immunology, The Scripps Research Institute, La Jolla, California, USA

    Bruce Beutler, Kasper Hoebe, Philippe Georgel & Xin Du

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  1. Bruce Beutler
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  2. Kasper Hoebe
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  3. Philippe Georgel
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  4. Xin Du
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Beutler, B., Hoebe, K., Georgel, P., Du, X. (2005). Forward Genetic Analysis of TLR Pathways. In: Toll and Toll-Like Receptors: An Immunologic Perspective. Molecular Biology Intelligence Unit. Springer, Boston, MA. https://doi.org/10.1007/0-387-27445-6_9

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