Oligonucleotide and complementary DNA microarrays are being used to subclassify histologically similar tumours, monitor disease progress, and individualize treatment regimens^{1, 2, 3, 4, 5}. However, extracting new biological insight from high-throughput genomic studies of human diseases is a challenge, limited by difficulties in recognizing and evaluating relevant biological processes from huge quantities of experimental data. Here we present a structured network knowledge-base approach to analyse genome-wide transcriptional responses in the context of known functional interrelationships among proteins, small molecules and phenotypes. This approach was used to analyse changes in blood leukocyte gene expression patterns in human subjects receiving an inflammatory stimulus (bacterial endotoxin). We explore the known genome-wide interaction network to identify significant functional modules perturbed in response to this stimulus. Our analysis reveals that the human blood leukocyte response to acute systemic inflammation includes the transient dysregulation of leukocyte bioenergetics and modulation of translational machinery. These findings provide insight into the regulation of global leukocyte activities as they relate to innate immune system tolerance and increased susceptibility to infection in humans.

1. Department of Surgery, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, New Jersey 08903, USA
2. Stanford Genome Technology Center, Palo Alto, California 94304, USA
3. Ingenuity Systems Inc, Mountain View, California 94043, USA
4. Departments of Molecular Genetics and Microbiology, and
5. Department of Surgery, University of Florida College of Medicine, Gainesville, Florida 32610, USA
6. Department of Surgery, Washington University in St Louis, St Louis, Missouri 63110, USA
7. Department of Surgery, University of Rochester School of Medicine, Rochester, New York 14642, USA
8. Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA
9. *These authors contributed equally to this work
10. Department of Surgery, University of Rochester School of Medicine, Rochester, New York 14642, USA
11. Department of Surgery, University of Pittsburgh School of Medicine, Pittsurgh, Pennsylvania 15213, USA
12. Pacific Northwest National Laboratory, Richland, Washington 99352, USA
13. Department of Statistics, University of Florida, Gainesville, Florida 32611, USA
14. Department of Surgery, University of Alabama School of Medicine, Birmingham, Alabama 35294, USA
15. Department of Biostatistics, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA
16. Department of Surgery, Washington University School of Medicine, St Louis, Missouri 63110, USA
17. Department of Surgery, Loyola University Stritch School of Medicine, Maywood, Illinois 60153, USA
18. Department of Surgery, University of Texas Medical Branch, Shriners Burns Hospital, Galveston, Texas 77550, USA
19. Department of Surgery, University of Washington Harborview Medical Center, Seattle, Washington 98104, USA
20. Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
21. Division of Trauma, Burns, and Critical Care, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
22. Department of Surgery, University of Colorado Denver Health Medical Center, Denver, Colorado 80204, USA
23. Burn Center and Division of Plastic Surgery, University of Washington Harborview Medical Center, Seattle, Washington 98104, USA
24. Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
25. Department of Surgery, University of Texas Houston Health Science Center, Houston Medical School, Houston, Texas 77030, USA
26. Department of Molecular Biology, Massachusetts General Hospital Harvard Medical School, Boston, Massachusetts 02114, USA
27. Department of Medical Science, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA
28. Department of Surgery, Northwestern University Medical School, Chicago, Illinois 60611, USA
29. Department of Biostatistics, University of Washington, Seattle, Washington 98195, USA
30. Center for Engineering in Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA
31. Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA
32. Lists of participants and affiliations appear at the end of the paper

Correspondence to: Ronald W. Davis² Correspondence and requests for materials should be addressed to R.W.D. (Email: dbowe@stanford.edu).

Received 17 May 2005; Accepted 4 July 2005

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