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Vol. LVIII, No. 1
January 13, 2006
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Beutler To Give Dyer Lecture, Jan. 18

Over the past two decades, Dr. Bruce Beutler has been a central figure in the innate immunity "renaissance." He will deliver the Jan. 18 R.E. Dyer Lecture, "Sensing Infection: Toll-Like Receptors and the Genetic Analysis of Mammalian Innate Immunity." It will be held at 3 p.m. in Masur Auditorium, Bldg. 10. Beutler is professor in the department of immunology at Scripps Research Institute, where he and his colleagues have established one of the most ambitious and successful mutagenesis efforts undertaken in mice, using the germline mutagen ENU to identify key components of the TLR signaling pathways, as well as genes required for resistance to viral pathogens.

Beutler was the first to isolate mouse tumor necrosis factor (TNF) and the first to recognize the role of TNF as a mediator of inflammation. Using TNF, he went on to identify the principal receptors through which animals sense microbial infections. This is widely regarded as one of the most fundamental advances in immunology and has opened a vibrant new field.

His work in innate immunity began in the 1980s when he isolated cachectin from lipopolysaccharide (LPS)-activated murine macrophages. By protein sequencing and cDNA cloning, he proved its identity to be TNF, the human ortholog of which was cloned contemporaneously by other investigators. Thus, Beutler was the first to realize that TNF could mediate diverse effects of LPS-induced shock. He proved this by passively immunizing mice against TNF and challenging them with LPS; that demonstrated them to be LPS-resistant. This established a causal link between TNF and inflammation and ignited widespread interest in the blockade of TNF for treatment of inflammation.

From 1986 to 1999 at UT Southwestern Medical Center and Howard Hughes Medical Institute in Dallas, Beutler studied the regulation of TNF biosynthesis. He initiated a classical genetic study in 1993 aimed at the positional cloning of two allelic mutations that rendered C3H/HeJ and C57BL/10ScCr mice entirely refractory to LPS. Utilizing TNF production as the signaling endpoint in genetic mapping, Beutler proved that the culpable mutations affected the gene encoding Toll-like receptor 4 (TLR4). The proof that TLR4 was an essential component of the mammalian LPS receptor led to the demonstration that other TLRs sense other conserved molecules of microbial origin and to our present understanding of how the host recognizes most infectious microbes.

Beutler is a strong advocate of the "phenotype first" approach that has brought biology some of its most spectacular gains. He has received many honors for his work, including the 2004 Robert Koch Prize, which he shared with Jules Hoffman and Shizuo Akira.

The R.E. Dyer lecture is part of the NIH Director's Wednesday Afternoon Lecture Series. No registration is required. For more information or reasonable accommodation call (301) 594-5595.

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