International Mammalian Genome Society

logo18th International Mouse Genome Conference

17-22 October 2004, Seattle, USA


ORAL PRESENTATION

THURSDAY OCTOBER 21

9.00am – 9.15am

A TLR2-RESPONSIVE LIPID EFFECTOR PATHWAY PROTECTS MAMMALS AGAINST GRAM-POSITIVE BACTERIAL SKIN INFECTIONS

Georgel P, Crozat K, Lauth X, Sovath S, Hoebe K, Du X, Rutschmann S, Jiang Z, Bigby T, Nizet V, Beutler B

1 TSRI, La Jolla, United States, 2 UCSD, San Diego, United States

Surface epithelia constitute the first line of defense against pathogens.  This defense may depend both upon barrier function and upon specific microbicidal effector molecules.  In the course of our germline mutagenesis effort, we isolated  flake (flk), an ENU-induced recessive mutation of C57BL/6 mice, which causes progressive alopecia and chronic exfoliative dermatitis.  These features appeared at weaning age and were more pronounced in older animals. Visible disruption of epidermal integrity and spontaneous skin infections requiring antibiotic therapy prompted us to examine the integrity of innate immune function in these mice. We utilized luminescence-tagged bacterial strains to monitor the progression of dermal infections in vivo and we showed that the flk mutation impairs the clearance of subcutaneous infections by Streptococcus pyogenes and Stapylococcus aureus:  Gram-positive pathogens that elicit innate immune responses by activating Toll-like receptor 2 (TLR2).  Positional cloning, sequencing and genetic complementation analysis revealed that flk is a novel allele of the steroyl CoA desaturase 1 gene (Scd1).  Flake homozygotes are unable to synthesize the monounsaturated fatty acids (MUFA) palmitoleate (C16:1) and oleate (C18:1), both of which are markedly cytotoxic to Gram-positive (but not Gram-negative) bacteria. Intradermal MUFA administration in S. aureus-infected mice improves bacterial clearance, and in normal mice, transcription of Scd 1- a gene with numerous NF-kB elements in its promoter - is strongly and specifically induced by TLR2 signaling.  These observations reveal the existence of a regulated, lipid-based antimicrobial effector pathway in mammals, and suggest new approaches to the treatment or prevention of Gram-positive bacterial infections.

[an error occurred while processing this directive]