Alexander Poltorak,
Xiaolong He,
*
Irina Smirnova,
Mu-Ya Liu,
Christophe Van Huffel,
Xin Du,
Dale Birdwell,
Erica Alejos,
Maria Silva,
Chris Galanos,
Marina Freudenberg,
Paola Ricciardi-Castagnoli,
Betsy Layton,
Bruce Beutler
§
Mutations of the gene Lps selectively impede
lipopolysaccharide (LPS) signal transduction in C3H/HeJ and
C57BL/10ScCr mice, rendering them resistant to endotoxin yet highly
susceptible to Gram-negative infection. The codominant
Lpsd allele of C3H/HeJ mice was shown to
correspond to a missense mutation in the third exon of the Toll-like
receptor-4 gene (Tlr4), predicted to replace proline with
histidine at position 712 of the polypeptide chain. C57BL/10ScCr mice
are homozygous for a null mutation of Tlr4. Thus, the
mammalian Tlr4 protein has been adapted primarily to subserve the
recognition of LPS and presumably transduces the LPS signal across the
plasma membrane. Destructive mutations of Tlr4 predispose to
the development of Gram-negative sepsis, leaving most aspects of immune
function intact.
A. Poltorak, X. He, I. Smirnova, M.-Y. Liu, C. Van Huffel, X. Du,
D. Birdwell, E. Alejos, M. Silva, B. Layton, B. Beutler, Howard Hughes
Medical Institute and the Department of Internal Medicine, University
of Texas Southwestern Medical Center, Dallas, TX 75235-9050 USA. C. Galanos and M. Freudenberg, Max-Planck Institute für
Immunobiologie, Freiburg, Germany. P. Ricciardi, CNR-Cellular and
Molecular Pharmacology Center, Milan, Italy.
*
Present address: Northwestern University, 2300 Children's Plaza, No.
209, Chicago, IL 60614-3394, USA.
Present address: University of Texas Southwestern Medical
Center, Department of Pharmacology, Dallas, TX 75235-9041 USA.
Present address: Millennium, Inc., Cambridge, MA 02139-4815,
USA.
§
To whom correspondence should be addressed at Howard Hughes
Medical Institute, 5323 Harry Hines Boulevard, Dallas, TX 75235-9050, USA.
