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Bruce Alan Beutler, M.D.
Professor
The Scripps Research Institute
Department of Immunology |
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PAST POSITIONS
| Professor |
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The University of Texas Southwestern Medical
Center at Dallas (1996 - 2000) |
| Associate Investigator |
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The Howard Hughes Medical Institute, Dallas (1991 - 2000) |
| Associate Professor |
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Department of Internal Medicine, U.T. Southwestern Medical
Center (1990 - 1996) |
| Assistant Professor |
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Department of Internal Medicine, U.T. Southwestern Medical
Center (1986 1990) |
| Assistant Investigator |
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Howard Hughes Medical Institute, Dallas, TX (1986 1991) |
| Assistant Professor |
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The Rockefeller University (1985 to 1986) |
| Associate Physician |
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Rockefeller University Hospital (1984 1986) |
| Fellow |
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The Rockefeller University (1983 -1985) |
| Resident |
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Department of Neurology, University of Texas, Southwestern
(1982 1983) |
| Intern |
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Department of Medicine, University of Texas, Southwestern
(1981 1982) |
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EDUCATION
Medical School: University of Chicago, M.D., 1981.
Undergraduate: University of California, San Diego (Revelle College),
B.A., 1976.
PRESENT RESEARCH INTERESTS
The role of cytokines in the inflammatory response, the molecular
genetics of innate immune reactions, and the phenotype-driven
analysis of immunity.
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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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