Influenza virus-induced brain-regulated acute phase responses (APR) include enhanced duration of non-rapid eye movement sleep (NREMS). The molecular pathways for these responses remain under investigated as do the brain anatomical pathways involved. Although influenza PR8 virus is considered non-neurotropic, recently we showed that upon intranasal challenge the virus localizes to the olfactory bulb (OB) and undergoes at least partial replication, as evidenced by expression of positive sense viral RNA in the OB, and up-regulates OB and hypothalamic (HT) cytokine expression. We investigate the hypothesis that the OB-HT pathway modulates the APR via molecular steps involving pathogen pattern recognition receptors in the OB, their induction of interleukin-1(IL1)-related molecules in the OB and HT and HT IL1/growth hormone releasing hormone (GHRH) mechanisms. Preliminary data;a) characterize a brain-specific IL1 receptor accessory protein (AcPb) that attenuates APRs, b) present a transgenic mouse expressing the IL1 type I receptor (ILRI) only on neurons, and c) show that mice lacking the GHRH receptor sleep less after viral challenge unlike any other mouse;previously we showed that GABAergic HT-neurons are receptive for both IL1 and GHRH. We propose three aims that will clarify the role of the OB-HT pathway in APR sleep responses.
Aim 1 tests the hypothesis that AcPb attenuates the APR-IL1 and sleep responses to viral challenge.
Aim 2 tests the hypothesis that PR-8- initiation of the APR sleep response is dependent upon OB glial expression of the ILRI.
Aim 3 tests the hypothesis that HT-GHRH/GHRH receptor mechanisms are critical to the flu-initiated sleep component of the APR. We develop an animal model that for the first time allows determination of the role of a brain-specific cytokine signaling mechanism, AcPb, in neuro-immune inflammatory processes. We characterize the relative contribution of the ILRI expression on neurons vs. glia in the APR sleep responses induced by virus. We make use of mice with a spontaneous mutation resulting in non-functional GHRH receptors to elaborate the OB-HT cytokine/GHRH mechanisms leading to APR sleep responses. Anticipated results will characterize OB involvement in the initiation of the APR and thereby provide a new readily accessible target for drug therapy and thus for the rapid translation of basic research to the clinic.

Public Health Relevance

These studies determine molecular mechanisms occurring in the olfactory bulb induced by influenza virus that are responsible for the viral-induced acute phase response including sleep. We examine the role of a brain- specific cytokine adaptor protein, called interleukin-1 receptor accessory protein (AcPb), in the brain regulation of sickness behavior. We also examine the specific roles neurons and glia play in this process. Further, we link the molecular events occurring in the olfactory bulb to the hypothalamus by characterizing the role the growth hormone releasing hormone receptor in sleep responses to influenza. Expected results will allow for the rapid translation of basic science to the clinic;e.. nasal application of AcPb to attenuate brain-regulated aspects of the cytokine storm.

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Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
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Special Emphasis Panel (ZRG1-IFCN-H (02))
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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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