Microbial Products and Cytokines in Sleep and Fever Regulation.

Excessive sleepiness and fever are constitutional symptoms associated with systemic infection. Although fevers have been investigated for many years, sleep responses to infectious challenge have only recently been investigated. Inoculation of animals with bacterial, viral, protozoan and fungal organisms result in complex sleep responses dependent upon the microbial agent and route of administration.

Influenza virus pathophysiology and brain invasion in mice with functional and dysfunctional Mx1 genes.

Mice with a dysfunctional myxovirus resistance-1 (dMx1) gene transport intranasally-instilled PR8 influenza virus to the olfactory bulb (OB) within 4 h post-infection. To determine if the presence of a functional Mx1 (fMx1) gene would influence this brain viral localization and/or disease, we infected mature C57BL/6 dMx1 and fMx1 mice under the same conditions and observed sickness behaviors, viral nucleoprotein (NP) RNA expression and innate immune mediator (IIM) mRNA expression in selected tissues at 15 and 96 h post-infection. Virus invaded the OB and lungs comparably in both sub-strains at 15 and 96 h as determined by nested PCR.

Neuroinflammation resulting from covert brain invasion by common viruses - a potential role in local and global neurodegeneration.

Neurodegenerative diseases are a horrendous burden for their victims, their families, and society as a whole. For half a century scientists have pursued the hypothesis that these diseases involve a chronic viral infection in the brain. However, efforts to consistently detect a specific virus in brains of patients with such diseases as Alzheimer's or multiple sclerosis have generally failed.

Attenuation of the influenza virus sickness behavior in mice deficient in Toll-like receptor 3.

Certain sickness behaviors occur consistently in influenza-infected humans and mice. These include body temperature changes, somnolence, and anorexia. Several cytokines serve as mediators of the influenza acute phase response (APR), including these sickness behaviors, and one likely inducer of these cytokines is dsRNA produced during viral replication.

Influenza virus- and cytokine-immunoreactive cells in the murine olfactory and central autonomic nervous systems before and after illness onset.

Influenza virus invades the olfactory bulb (OB) and enhances cytokine mRNAs therein at the time of illness onset. Here we show that viral antigen immunoreactivity co-localized with glial markers in the OB but could not be detected in other brain areas. Interleukin 1beta- and tumor necrosis factor alpha-immunoreactivity co-localized with neuronal markers in olfactory and central autonomic systems, and the number of cytokine-immunoreactive neurons increased at the time of illness onset [15 h post-inoculation (PI)] but not before (10 h PI).

Spontaneous and influenza virus-induced sleep are altered in TNF-alpha double-receptor deficient mice.

Tumor necrosis factor-alpha (TNF-alpha) is associated with sleep regulation in health and disease. Previous studies assessed sleep in mice genetically deficient in the TNF-alpha 55-kDa receptor. In this study, spontaneous and influenza virus-induced sleep profiles were assessed in mice deficient in both the 55-kDa and 75-kDa TNF-alpha receptors [TNF-2R knockouts (KO)] and wild-type (WT) strain controls.

Interferon type I receptor-deficient mice have altered disease symptoms in response to influenza virus.

The role of type I interferons (IFNs) in mediation of acute viral symptoms (fever, somnolence, anorexia, etc.) is unknown. To determine the role of type I IFN in selected symptom development, body temperature and sleep responses to a marginally lethal dose of X-31 influenza virus were examined in mice with a targeted mutation of the IFN receptor type I (IFN-RI knockouts) and compared to wild-type 129 SvEv control mice.

Links between the innate immune system and sleep.

Sleep is a fundamental physiologic process with unknown functions. It is divided into 2 distinct states: non-rapid-eye-movement sleep and rapid-eye-movement sleep. After acute infection with nonneurotropic agents, there are stereotypic changes in non-rapid-eye-movement sleep, particularly increased time spent in slow-wave sleep, and often a reduction of time spent in rapid-eye-movement sleep.

Sleep and body temperature responses in an acute viral infection model are altered in interferon type I receptor-deficient mice.

Type I interferons (IFNs) include IFNalpha and IFNbeta, both of which are elevated in acute viral infections and both of which have been shown to induce symptoms such as fever and somnolence when administered in pharmacological doses. To investigate the role of type I IFNs in mediation of acute respiratory viral symptoms we examined sleep and body temperature responses in mice with a targeted mutation of the IFN receptor type I (IFN-RI knockouts). IFN-RI knockouts (KOs) or wild-type 129 SvEv controls were challenged intratracheally (IT) with combined poly[rI.

Influenza virus-induced glucocorticoid and hypothalamic and lung cytokine mRNA responses in dwarf lit/lit mice.

Influenza virus infection up-regulates cytokines such as interleukin-1beta (IL-1beta) and activates the somatotropic axis and the hypothalamic-pituitary axis. Mice with deficits in growth hormone releasing hormone (GHRH) signaling (lit/lit mice) respond to influenza virus challenge with a progressive decrease in sleep and lower survival rates. Current experiments characterize plasma glucocorticoid responses and hypothalamic and lung mRNA expression of sleep-related genes in lit/lit mice and their heterozygous controls after influenza virus challenge.

Influenza virus-induced sleep responses in mice with targeted disruptions in neuronal or inducible nitric oxide synthases.

Influenza viral infection induces increases in non-rapid eye movement sleep and decreases in rapid eye movement sleep in normal mice. An array of cytokines is produced during the infection, and some of them, such as IL-1beta and TNF-alpha, are well-defined somnogenic substances. It is suggested that nitric oxide (NO) may mediate the sleep-promoting effects of these cytokines.

The role of nitric oxide synthases in the sleep responses to tumor necrosis factor-alpha.

It is well established that cytokines such as tumor necrosis factor-alpha (TNFalpha) and interleukin-1beta (IL-1beta) are involved in physiological sleep regulation, yet their downstream somnogenic mechanisms remain largely uninvestigated. Nitric oxide (NO) is an effector molecule for some TNFalpha actions. Neuronal nitric oxide synthase (nNOS) and inducible nitric oxide synthase (iNOS) gene knockout (KO) mice sleep differently than their respective controls.

Intratracheal double-stranded RNA plus interferon-gamma: a model for analysis of the acute phase response to respiratory viral infections.

Double-stranded (ds)RNA is made as a by-product of viral replication. Synthetic dsRNA induces virtually all of the same systemic symptoms as acute viral infections, such as fever and malaise. In order to develop a model of respiratory viral infections (such as influenza) suitable for use in gene knockout mice (where the deleted gene may affect viral replication), we examined C57BL/6 mouse body temperature and locomotor activity responses to the synthetic dsRNA polyriboinosinic.

Animal models for hemorrhage and resuscitation research.

Background: This report summarizes recent workshop discussions on animal models for hemorrhage and resuscitation research, and it is supplemented with relevant current literature. The emphasis is on models for casualty care on the battlefield.

Results: Current animal models of hemorrhage and resuscitation vary substantially from one laboratory to another, and are not based on clinical experience.

Spontaneous sleep in mice with targeted disruptions of neuronal or inducible nitric oxide synthase genes.

Nitric oxide (NO) affects almost every physiological process, including the regulation of sleep. There is strong evidence that NO plays an important role in rapid eye movement sleep (REMS) regulation. To further investigate the role of NO in sleep, we characterized spontaneous sleep in mice with targeted disruptions (knockout; KO) in the neuronal nitric oxide synthase (nNOS) or inducible (i)NOS genes.

Sleep in host defense.

Sleep remains an important enigma in neurobiology; it has a robust adaptive value yet its function remains elusive. Changes in sleep are hallmarks of the acute phase response to infectious challenge. The molecular regulation of these responses involves a cytokine cascade within brain, including interleukin-1 and tumor necrosis factor, and several other substances such as growth hormone releasing hormone, prolactin, nitric oxide and nuclear factor kappaB.

Alterations in EEG activity and sleep after influenza viral infection in GHRH receptor-deficient mice.

Viral infections induce excess non-rapid eye movement sleep (NREMS) in mice. Growth hormone-releasing hormone receptor (GHRH receptor) was previously identified as a candidate gene responsible for NREMS responses to influenza challenge in mice. The dwarf lit/lit mouse with a nonfunctional GHRH receptor was used to assess the role of the GHRH receptor in viral-induced NREMS.