Molecular Mechanisms of Sleep Responses to Viral Infection

描述（由申请人提供）：流感病毒诱导的脑调节急性期反应（APR）包括非快速眼动睡眠（NREMS）持续时间的增加。这些反应的分子途径和涉及的脑解剖途径仍在研究中。虽然流感PR8病毒被认为是非嗜神经性的，但最近我们发现，在鼻内攻击时，病毒定位于嗅球（OB）并进行至少部分复制，这一点通过嗅球中阳性感觉病毒RNA的表达得到证实，并上调嗅球和下丘脑（HT）细胞因子的表达。我们研究了OB- ht通路通过OB中病原体模式识别受体的分子步骤调节APR的假设，OB中病原体模式识别受体诱导白细胞介素-1（il -1）相关分子

DESCRIPTION (provided by applicant): 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.