Regental Professor and Director
Center for Genetics of Host Defense at the University of Texas Southwestern Medical Center in Dallas, Texas, USA.
Raymond and Ellen Willie Distinguished Chair in Cancer Research in Honor of Laverne and Raymond Willie, Sr.
Among the largest issues in immunology is the question of self/non-self discrimination. How do we \"know\" when we have an infection? What are the receptors that alert us? For more than a century, and in fact, since microbes were recognized as the cause of infections, it has been clear that mammals are genetically programmed to recognize them. Moreover, it has long been an obvious corollary that certain molecules of microbial origin must trigger a host response, and that specialized receptors of the host must mediate recognition of these molecules. This, after all, is how biological systems operate. But what were these receptors? A genetic approach was required to answer the question.
Because the innate immune system must act promptly to contain an infection, mammals respond violently to purified molecules of microbial origin such as endotoxin (lipopolysaccharide; LPS). LPS has been investigated for many decades as a prototypic inducer of innate responses. And it has long been known that sensing LPS is required for a mouse to overcome a Gram-negative infection. It has also been clear that cytokines, produced by mononuclear phagocytes in response to LPS, orchestrate the innate response and can be highly toxic when produced in large amounts. But the nature of the LPS receptor, which ignites the entire process, was long elusive.
The present activities of the Beutler laboratory stem from a longstanding interest in innate immune sensing and response, and involve the use of positional cloning as a method to decipher it. In 1998, the laboratory identified the mammalian LPS receptor as Toll-like receptor 4 (TLR4) by genetically mapping and then cloning a mutant allele known as Lpsd, which in homozygous form caused unresponsiveness to LPS in mice. This discovery-the first assignment of function to a TLR-led directly to the present concept that the mammalian TLRs serve as sensors of microbial infection. It is now believed that each of the 12 mouse TLRs and 10 human TLRs dectect a limited number of the signature molecules that herald infection (LPS, lipopeptides, flagellin, unmethylated DNA, dsRNA, and ssRNA begin the best known examples). They may also detect molecular ligands of host origin under some circumstances, and may participate in sterile inflammation (observed in autoimmune diseases). The TLRs are the gatekeepers of the most powerful inflammatory responses known, and as such, are probably important in a wide range of diseases. And without TLR signaling, a state of severe immunocompromise exists.
The Beutler laboratory systematically employs a forward genetic approach to identify genes that are essential for the mammalian innate immune response, and to determine their functions relative to one another. The forward genetic approach entails the induction of thousands of random germline point mutations on a defined genetic background (C57BL/6) using N-ethyl-N-nitrosourea (ENU), the phenotypic screening of many thousands of mice for specific defects of immunity, and the positional cloning of those transmissible mutations that are detected. This classical genetic method does not depend upon hypotheses, nor upon assumptions about how innate immunity \"should\" work. Hence, it is unbiased, and errors of interpretation are extremely rare.
Over time, the effects of hundreds of millions of point mutations that change coding sense have been probed, and approximately 70% of all genes have so far been mutated to a state of detectable phenovariance. In terms of throughput, the ENU mutagenesis effort now underway in the Beutler laboratory is the largest in the world, and presently the only one primarily devoted to the decipherment of innate immunity.
2011 Nobel Prize in Physiology or Medicine with Jules A. Hoffmann and Ralph M. Steinman
Shaw Prize (2011, shared with Jules A. Hoffmann and Ruslan M. Medzhitov)
2009 Albany Medical Center Prize
2007 Frederik B. Bang Award (International Endotoxin and Innate Immunity Society)
2007 Doctor of Medicine honoris causa from the Technical University of Munich
2007 Balzan Prize (International Balzan Foundation, Italy and Switzerland)
2006 Gran Prix Charles-Leopold-Mayer (Académie des Sciences, France)
2006 William B. Coley Award (Cancer Research Institute, USA)
2004 Robert Koch Prize (Robert Koch Stiftung, Germany)
1994 Outstanding Investigator Award (American Federation for Clinical Research, USA)
Beutler,B., Mahoney,J., Le Trang,N., Pekala,P. and Cerami,A. (1985) Purification of cachectin, a lipoprotein lipase-suppressing hormone secreted by endotoxin-induced RAW 264.7 cells. J. Exp. Med. 161:984-995.
Beutler,B., Greenwald,D., Hulmes,J.D., Chang,M., Pan,Y.-C.E., Mathison,J., Ulevitch,R. and Cerami,A. (1985) Identity of tumour necrosis factor and the macrophage-secreted factor cachectin. Nature 316:552-554.
Beutler,B., Milsark,I.W. and Cerami,A. (1985) Passive immunization against cachectin/tumor necrosis factor (TNF) protects mice from the lethal effect of endotoxin. Science 229:869-871.
Poltorak,A., He,X., Smirnova,I., Liu,M.-Y., Van Huffel,C., Du,X., Birdwell,D., Alejos,E., Silva,M., Galanos,C., Freudenberg, M.A., Ricciardi-Castagnoli, P., Layton, B. and Beutler, B.(1998) Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282:2085-2088.
Beutler,B., Jiang,Z., Georgel,P., Crozat,K., Croker,B., Rutschmann,S., Du,X. and Hoebe,K. (2006) Genetic analysis of host resistance: Toll-Like receptor signaling and immunity at large. Annu. Rev. Immunol. 24:353-389.
Hoebe,K., Du,X., Georgel,P., Janssen,E., Tabeta,K., Kim,S.O., Goode,J., Lin,P., Mann,N., Mudd,S., Crozat, K., Sovath, S., Han, J. and Beutler, B. (2003) Identification of Lps2 as a key transducer of MyD88-independent TIR signaling. Nature 424:743-748.
Hoebe,K., Georgel,P., Rutschmann,S., Du,X., Mudd,S., Crozat,K., Sovath,S., Shamel,L., Hartung,T., Zahringer,U. and Beutler, B. (2005) CD36 is a sensor of diacylglycerides. Nature 433:523-527.
Tabeta,K., Hoebe,K., Janssen,E.M., Du,X., Georgel,P., Crozat,K., Mudd,S., Mann,N., Sovath,S., Goode,J., Shamel, L., Herskovits, A. A., Portnoy, D. A., Cooke, M., Tarantino, L. M., Wiltshire, T., Steinberg, B. E., Grinstein, S. and Beutler, B. (2006) The Unc93b1 mutation 3d disrupts exogenous antigen presentation and signaling via Toll-like receptors 3, 7 and 9. Nat. Immunol. 7:156-164.
Jiang, Z., Georgel, P., Li, C., Choe, J., Crozat, K., Rutschmann, S., Du, X., Bigby, T., Mudd, S., Sovath, S., Wilson, I. A., Olson, A. and Beutler, B. (2006) Details of Toll-like receptor:adapter interaction revealed by germ-line mutagenesis, Proc Natl Acad Sci U S A 103, 10961-10966.
Jiang, Z., Georgel, P., Du, X., Shamel, L., Sovath, S., Mudd, S., Huber, M., Kalis, C., Keck, S., Galanos, C., Freudenberg, M. and Beutler, B. (2005) CD14 is required for MyD88-independent LPS signaling, Nat. Immunol. 6, 565-570.
Crozat, K., Georgel, P., Rutschmann, S., Mann, N., Du, X., Hoebe, K. and Beutler, B. (2006) Analysis of the MCMV resistome by ENU mutagenesis, Mamm. Genome 17, 398-406.
Croker, B., Crozat, K., Berger, M., Xia, Y., Sovath, S., Schaffer, L., Eleftherianos, I., Imler, J. L. and Beutler, B. (2007) ATP-sensitive potassium channels mediate survival during infection in mammals and insects, Nat. Genet. 39, 1453-1460.
Gavin, A. L., Hoebe, K., Duong, B., Ota, T., Martin, C., Beutler, B. and Nemazee, D. (2006) Adjuvant-enhanced antibody responses in the absence of toll-like receptor signaling, Science 314, 1936-1938.
Janssen, E., Tabeta, K., Barnes, M. J., Rutschmann, S., McBride, S., Bahjat, K. S., Schoenberger, S. P., Theofilopoulos, A. N., Beutler, B. and Hoebe, K. (2006) Efficient T cell activation via a Toll-Interleukin 1 Receptor-independent pathway, Immunity 24, 787-799.
Du, X., She, E., Gelbart, T., Truksa, J., Lee, P., Xia, Y., Khovananth, K., Mudd, S., Mann, N., Moresco, E. M., Beutler, E. and Beutler, B. (2008) The serine protease TMPRSS6 is required to sense iron deficiency, Science 320, 1088-1092.
Croker, B. A., Lawson, B. R., Berger, M., Eidenschenk, C., Blasius, A. L., Moresco, E. M., Sovath, S., Cengia, L., Shultz, L. D., Theofilopoulos, A. N., Pettersson, S. and Beutler, B. A. (2008) Inflammation and autoimmunity caused by a SHP1 mutation depend on IL-1, MyD88, and a microbial trigger, Proc. Natl. Acad. Sci. ,USA 105,15028-15033.