Fatigue, excessive sleepiness, excess sleep, and sleep disturbances are presenting symptoms in nearly all infectious diseases. The broad objective of this proposal is to characterize the molecular mechanisms responsible for changes in sleep induced by influenza virus. We hypothesize that viral double-stranded (ds) RNA is produced in infected cells and it, in turn, induces an upregulation of cytokines including interferons (IFN). The cytokines then induce growth hormone releasing hormone (GHRH) release and it, via nitric oxide (NO), enhances sleep. Substantial preliminary data support this hypothesis. The model used in the proposed studies is A/PR/8/34-HIN1 influenza virus infection in the mouse. PR8 causes a pneumonitis accompanied by early onset of sleep responses.
In Specific Aim #1, a comparison will be made using gene arrays of the time courses of cytokines induced by pure influenza virus and dsRNA in lung and brain. We expect a similar cytokine profile after both stimuli.
In Specific Aim #2 the role of the GHRH receptor in viral-induced sleep responses will be determined. Preliminary data indicate that mice lacking a functional GHRH receptor sleep less, rather than more, after viral challenge. We anticipate that that finding will be confirmed and that GH replacement therapy will not alter the virus-induced sleep responses, but may reduce mortality.
In Specific Aim #3, nitric oxide synthase knockout mice will be used to investigate the role of NO in viral-induced sleep. Preliminary data indicate an attenuated sleep response after host challenge in NOS-2 (inducible NOS) knockout mice.
In Specific Aim #4, IFN receptor (types I and II) knockout mice will be used to investigate the role of IFNs in viral-induced sleep.
In Specific Aims 2, 3, and 4 we anticipate that the cytokine gene profiles induced by virus in the mutant strain will be different from controls and will reflect the different sleep responses induced by virus in these mutant strains of mice.
In Specific Aim #5, we will investigate, in vitro, the role of virus-associated dsRNA in cytokine induction by influenza. Since we hypothesize that dsRNA upregulates cytokines via nuclear factor kappa B (NFKB) we will determine what other activators of NFKB, e.g., free radicals, do to NFKB activation in murine macrophages and how pharmacological blockers affect viral-induced activation of NFKB and the cytokine cascade. The anticipated results will greatly aid our understanding of the molecular mechanisms involved in viral-induced sleep responses and other facets of the acute phase response.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Special Emphasis Panel (ZRG1-IFCN-2 (01))
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Willinger, Marian
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Washington State University
Veterinary Sciences
Schools of Veterinary Medicine
United States
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