6th The Awaji International Forum on Infection and Immunity  
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Bruce Alan Beutler, M.D.

The Scripps Research Institute
Department of Immunology

The University of Texas Southwestern Medical Center at Dallas (1996 - 2000)
Associate Investigator
  The Howard Hughes Medical Institute, Dallas (1991 - 2000)
Associate Professor
  Department of Internal Medicine, U.T. Southwestern Medical Center (1990 - 1996)
Assistant Professor
  Department of Internal Medicine, U.T. Southwestern Medical Center (1986 1990)
Assistant Investigator
  Howard Hughes Medical Institute, Dallas, TX (1986 1991)
Assistant Professor
  The Rockefeller University (1985 to 1986)
Associate Physician
  Rockefeller University Hospital (1984 1986)
  The Rockefeller University (1983 -1985)
  Department of Neurology, University of Texas, Southwestern (1982 1983)
  Department of Medicine, University of Texas, Southwestern (1981 1982)


Medical School: University of Chicago, M.D., 1981.
Undergraduate: University of California, San Diego (Revelle College), B.A., 1976.

The role of cytokines in the inflammatory response, the molecular genetics of innate immune reactions, and the phenotype-driven analysis of immunity.

Selected publications

1. B. Beutler, J. Mahoney, N. Le Trang, P. Pekala and A. Cerami. Purification of cachectin, a lipoprotein lipase suppressing hormone secreted by endotoxin induced RAW 264.7 cells. J.Exp.Med. 161:984 995, (1985).
2. B. Beutler, D. Greenwald, J.D. Hulmes, M. Chang, Y. C.E. Pan, J. Mathison, R. Ulevitch and A. Cerami. Identity of tumour necrosis factor and the macrophage secreted factor cachectin. Nature 316:552 554, (1985).
Publications #1and #2 describe the de novo isolation of mouse tumor necrosis factor, based on a non-classical biological assay (suppression of lipoprotein lipase synthesis by fat cells). This work suggested than many LPS-induced biological responses were mediated by a single cytokine, and set the stage for subsequent studies in which TNF was shown to be an inflammatory mediator.
3. B. Beutler, I.W. Milsark and A. Cerami. Passive immunization against cachectin/tumor necrosis factor (TNF) protects mice from the lethal effect of endotoxin. Science 229:869 871, (1985).This work revealed that TNF was a key mediator of endotoxic shock, and stands as the first demonstration of its in vivo inflammatory activity. It provided the conceptual basis for future efforts at TNF neutralization with therapeutic intent.
4. D. Caput, B. Beutler, K. Hartog, S. Brown Shimer and A. Cerami. Identification of a common nucleotide sequence in the 3' untranslated region of mRNA molecules specifying inflammatory mediators. Proc.Natl.Acad.Sci.U.S.A. 83:1670 1674, (1986). This paper is the first to report the presence of the UA-rich element in cytokine mRNAs, later shown to confer mRNA instability and translational suppression.
5. K. Peppel, D. Crawford, and B. Beutler. A tumor necrosis factor (TNF) receptor IgG heavy chain chimeric protein as a bivalent antagonist of TNF activity. J.Exp.Med. 174:1483 1489, (1991). The invention, expression, physical characteristics, and in vivo use of a recombinant TNF inhibitor are described. As Enbrel, the equivalent molecule later found wide use in the treatment of rheumatoid arthritis and other inflammatory diseases.
6. A. Poltorak, X. He, I. Smirnova, M.-Y. Liu, C. Van Huffel, X. Du, D. Birdwell, E. Alejos, M. Silva, C. Galanos, M. Freudenberg, P. Ricciardi-Castagnoli, B. Layton, and B. Beutler. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: Mutations in the TLR4 gene. Science 282: 2085-2088, (1998). Through positional cloning, TLR4 was identified as the core element of the LPS receptor, required for all responses to LPS including toxic and protective responses and adjuvanticity. A receptor for LPS had long been assumed to exist, but its membrane-spanning component could not be identified through other means. This was the first assignment of function to a mammalian TLR. It immediately suggested that each TLR might sense a small collection of broadly conserved molecules of microbial orgin, and implied that TLRs were the key sensors used by the mammalian innate immune system to detect infection. At present, this paper is more highly cited than any other publication in the TLR field.
7. A. Poltorak, P. Ricciardi-Castagnoli, S. Citterio, and B. Beutler. Physical contact between LPS and TLR4 revealed by genetic complementation. Proc.Natl.Acad.Sci. U.S.A. 97:2163-2167, (2000). This work strongly implied that direct contact between LPS and TLR4 must take place for signaling to occur.
8. Smirnova, N. Mann, A. Dols, H.H. Derkx, M. Hibberd, M. Levin, and B. Beutler. Assay of locus-specific genetic load implicates rare TLR4 mutations in meningococcal susceptibility. Proc.Natl.Acad.Sci. U.S.A. 100:6075-6080, (2003). Large-scale sequencing revealed that patients with meningococcal sepsis have a highly significant excess of rare coding changes (but not synonymous or common changes) within the TLR4 protein. It is inferred that rare, codominant TLR4 mutations of recent origin contribute to Gram-negative susceptibility: a pattern later found to apply in other fields as well (e.g., with regard to proteins required for uptake of cholesterol in patients with hypercholesterolemia).
9. K. Hoebe, X. Du, P. Georgel, K. E. Janssen, Tabeta, S. Kim, J. Goode, P. Lin, N. Mann, S. Mudd, K. Crozat, S. Sovath and B. Beutler. Identification of Lps2 as a key transducer of MyD88-independent TIR signalling. Nature 424:743-748, (2003). Through random germline mutagenesis and phenotypic screening, the authors created a new phenotype in which MyD88-independent TLR signaling was abolished. By positional cloning, they identified a new TIR adaptor protein required for MyD88-independent signaling, now known as TRIF or TICAM-1. This work also revealed, for the first time, the importance of TLR signal transduction in the containment of viral infection in vivo.
10. K. Hoebe, E.M. Janssen, S.O. Kim, L. Alexopoulou, R.A. Flavell, J. Han and B. Beutler. Upregulation of costimulatory molecules induced by lipopolysaccharide and double-stranded RNA occurs by Trif-dependent and Trif-independent pathways. Nature Immunol. 4:1223-1229, (2003). This paper stands as the first demonstration of a TLR3- and TRIF-independent pathway for dsRNA sensing.
11. K. Hoebe, P. Georgel, S. Rutschmann, X. Du, S. Mudd, K. Crozat, S. Sovath, L. Shamel, T. Hartung,U. Zähringer, and B. Beutler. CD36 is a sensor of diacylglycerides. Nature 433:523-527, (2005). Using ENU mutagenesis, the authors identified a phenotype in which diacyl-lipopetide sensing was suppressed. The sensing of diacyl-lipopeptides and LTA was then shown to depend upon CD36, which was thereby identified as a coreceptor within the TLR2/TLR6 complex.
12. Z. Jiang, P. Georgel, X. Du, L. Shamel, S. Sovath, S. Mudd, and B. Beutler. CD14 is required for MyD88-independent LPS signaling. Nature Immunology 6:565-570, (2005). The ENU-induced phenotype Heedless was identified as a mutation in CD14, revealing that CD14 is not required for LPS signaling per se, but only for smooth LPS signaling (lipid A can signal via the MyD88/Mal pathway in the absence of CD14). This, in turn, suggests that CD14 exerts a qualitative effect on the TLR4 complex through interaction with the TLR4 ectodomain.
13. K. Tabeta, K. Hoebe, E. M Janssen, X. Du, P. Georgel, K. Crozat, S. Mudd, N. Mann, S. Sovath, J. Goode, L. Shamel, A. Herskovits, D. Portnoy, M. Cooke, L. M. Tarantion, T. Wiltshire, B. E. Steinberg, S. Grinstein, and B. Beutler. The Unc93b1 mutation 3d disrupts exogenous antigen presentation signaling via Toll-like receptors 3, 7 and 9. Nature Immunology 7:156-164, (2006). The ENU-induced 3d mutation revealed that UNC-93B, previously a protein of unknown function, is required for nucleic acid sensing by the endosomal Toll-like receptors as well as exogenous antigen presentation. Because UNC-93B is an intrinsic protein of the ER, an ER-derived signal must influence endosomal events, and is absolutely required for TLR3, TLR7, and TLR9 signaling. This paper has opened a new question in cell biology, and re-affirms the importance of the classical genetic approach.
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