Influenza is a respiratory viral infection often accompanied by severe symptoms such as high fevers and a profound need to sleep. Collectively, these symptoms are part of the acute phase response (APR). The understanding of the molecular mediators of the viral APR is in its infancy. Some of the progress made in deciphering centrally regulated APRs resulted from research supported by this grant. Our accomplishments include;showing that sleep changes over the course of an influenza virus infection;demonstrating that a toxic viral by-product, double-stranded (ds) RNA, is found in lungs of infected mice and that it induces the APR;characterizing the influenza APR in mice, and investigating APR molecular mechanisms through development of appropriate infection models and using genetically-deficient mice. Most importantly, we recently demonstrated that strains of human influenza .previously considered incapable of accessing the mouse brain, in fact do so within a few hours following intranasal infection. In brain, viral RNA and viral antigen are accompanied by induction of cytokines with the potential for mediating the APR. We expand upon these data in Aims 1 and 2.
Aim 1 addresses the general hypothesis that virus, viral proteins and/or viral RNA pass from the nasal cavities to the olfactory bulb (OB) via the olfactory nerve and induce cytokine production. We will use immunohistochemistry, polymerase chain reaction techniques, and electron microscopy to determine the time course of viral invasion of the OB and its relationship to cytokine expression. Double-labeling techniques will be used to determine co-localization of virus protein with cytokines and the cell types expressing cytokines and containing virus proteins.
Aim 2 tests the hypothesis that OB-expressed cytokines activate hypothalamic (HT) cytokines and subsequent HT-regulated APRs. The timing of HT cytokine expression relative to OB expression will be determined. The effects of TNFa injection into the OB and the effects of cutting OB-brain connections on HT-cytokine and sleep and fever responses will be determined.
Aim 3 tests the general hypothesis that invasion of the CNS by influenza virus is affected by immune status of the host. We determine whether homologous immunity to influenza virus offers partial protection against viral invasion of the brain. The measures made in Aim 1 will be used in Aims 2 and 3 along with sleep, body temperature, locomotor activity and body weight determinations.
Aim 4 is derived from our past work showing that viral dsRNA induces flu-like symptoms. Thus mice deficient in toll- like receptor 3 (TLR3), a receptor that binds dsRNA, will be challenged with virus. APRs including sleep and brain cytokine expression will be determined. There is an association between upper respiratory viral infections and sudden infant death syndrome (SIDS);SIDS occurs during sleep and is associated with sleep abnormalities. The proposed work will provide insights into how viruses induce disease symptoms as well as such complications as SIDS and viral encephalitis/encephalopathy.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Neuroendocrinology, Neuroimmunology, and Behavior Study Section (NNB)
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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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