Trends in Genetics
Volume 15, Issue 8, 1 August 1999, Pages 291-294
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Host resistance to infection: genetic control of lipopolysaccharide responsiveness by Toll-like receptor genes

https://doi.org/10.1016/S0168-9525(99)01782-5Get rights and content

Abstract

Gram-negative bacterial lipopolysaccharide evokes a protective inflammatory response in the normal host. Through genetic analysis of mutant mice, the gene encoding Toll-like receptor 4 (Tlr4) was recently identified as a critical component of this host defense mechanism. Tlr4 is a member of an ancient gene family that regulates antimicrobial host defense in plants, invertebrates and mammals.

Section snippets

Identification and characterization of the Lpsd phenotype

In 1968, Sultzer demonstrated that the C3H/HeJ inbred mouse strain was naturally tolerant to the proinflammatory properties of LPS (Ref. 5). Remarkably, these mice can withstand a purified LPS challenge of 20–40 times the median lethal dose for most other laboratory strains. Initial mapping studies confirmed the monogenic basis of this phenotype, and linked it to the major urinary protein locus (Mup1) on chromosome 4, with the designation Lps. The vast majority of inbred strains are

Cloning of the Lps gene

Discovering the molecular basis of the the Lps gene defect is of great interest because it will provide a key insight into biochemical pathways leading to cellular activation in response to LPS (Ref. 6). Virulent Gram-negative bacteria induce inflammation by shedding LPS from their outer membrane. Within the aqueous environment of the host’s vascular compartment, these amphipathic molecules spontaneously aggregate as micelles. Plasma LPS-binding protein (LBP) catalytically transfers LPS

Characteristics of the Tlr gene family

A family of Toll-like genes that participate in host defense in insects, plants and mammals has been recognized (Table 1). A distinctive structural feature of the Toll-like receptor family is the novel coupling of leucine-rich repeats (LRRs) with a domain that is homologous to the cytoplasmic portion of the IL-1R, now termed the Toll–IL-1R homology domain [TIR domain (Ref. 22 and Fig. 1a). The LRR is a widely dispersed motif found in over 70 proteins of diverse function and origin and has been

Host defense functions of Toll-like receptors

In Drosophila, loss-of-function Toll mutations block dorsoventral signaling during embryonic development24. Impaired activation of REL-type transcription factors in adult Toll mutants renders them susceptible to Aspergillus fumigatus infection by inhibiting the production of the antifungal peptide Drosomycin12. Mutation of 18-wheeler, a Drosophila Toll homolog that activates the REL protein Dorsal-like immunity factor (Dif), also compomises antibacterial host defense13. Several cytoplasmic

Future directions

Clearly, the understanding of the role of Toll-like receptor molecules in host defense is in its infancy. Compelling data from plant, invertebrate and mammalian systems have implicated members of this family as ancient immunologic guardians, steadfastly defending the host against the continuous threat of microbial invasion. Fundamental questions concerning the vertebrate Toll-like receptors abound. For example, what mechanisms specify pathogen recognition, which accessory molecules are required

Acknowledgements

D.M. is a Scholar of Fonds de la Recherche en Santé du Québec (FRSQ). P.G. is an International Research Scholar of the Howard Hughes Medical Institute and a Senior Scientist of the MRC. S.T.Q. is a recipient of a Clinician Scientist Award from the MRC and a Career Award in the Biomedical Sciences from the Burroughs Wellcome Fund.

References (24)

  • E.T. Reitschel

    Bacterial endotoxin: molecular relationships of structure to activity and function

    FASEB J.

    (1994)
  • D.L. Rosenstreich

    Genetic control of endotoxin response: C3H/HeJ mice

  • Cited by (0)

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