The host response to smallpox: Analysis of the gene expression program in peripheral blood cells in a nonhuman primate model
- Kathleen H. Rubins*,†,
- Lisa E. Hensley‡,
- Peter B. Jahrling‡,
- Adeline R. Whitney*,§,
- Thomas W. Geisbert‡,
- John W. Huggins‡,
- Art Owen¶,
- James W. LeDuc∥,
- Patrick O. Brown†,**,††, and
- David A. Relman*,‡‡,§§,††
- Departments of *Microbiology and Immunology, †Biochemistry, ¶Statistics, and ‡‡Medicine and **Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305; ‡U.S. Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702; ∥Centers for Disease Control and Prevention, Atlanta, GA 30333; and §§Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304
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Contributed by Patrick O. Brown, August 17, 2004
Abstract
Smallpox has played an unparalleled role in human history and remains a significant potential threat to public health. Despite the historical significance of this disease, we know little about the underlying pathophysiology or the virulence mechanisms of the causative agent, variola virus. To improve our understanding of variola pathogenesis and variola-host interactions, we examined the molecular and cellular features of hemorrhagic smallpox in cynomolgus macaques. We used cDNA microarrays to analyze host gene expression patterns in sequential blood samples from each of 22 infected animals. Variola infection elicited striking and temporally coordinated patterns of gene expression in peripheral blood. Of particular interest were features that appear to represent an IFN response, cell proliferation, immunoglobulin gene expression, viral dose-dependent gene expression patterns, and viral modulation of the host immune response. The virtual absence of a tumor necrosis factor α/NF-κB-activated transcriptional program in the face of an overwhelming systemic infection suggests that variola gene products may ablate this response. These results provide a detailed picture of the host transcriptional response during smallpox infection, and may help guide the development of diagnostic, therapeutic, and prophylactic strategies.
Footnotes
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↵ †† To whom correspondence may be addressed. E-mail: pbrown{at}pmgm2.stanford.edu or relman{at}pmgm2.stanford.edu.
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↵ § Present address: Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 903 South 4th Street, Hamilton, MT 59840.
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Abbreviations: PBMC, peripheral blood mononuclear cell; TNF-α, tumor necrosis factor α; pfu, plaque-forming unit(s).
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See Commentary on page 14994.
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Freely available online through the PNAS open access option.
- Copyright © 2004, The National Academy of Sciences
