Sleep and Fatigue during Chronic Viral Infection.

Abstract

INTRODUCTION: Human gammaherpesvirus (GHV) infections, such as with Epstein-Barr Virus (EBV), are associated with fatigue and elevated concentrations of cytokines. Murine GHV-68 (MuGHV) has been used as a model of EBV. However, the behavioral impact of infection with MuGHV is unknown. METHODS: Male C57BL/6J mice (25 – 28 g at time of surgery) were housed in cages containing running wheels and infrared detectors to measure activity. Mice were administered vehicle intranasally (I.N.) at dark onset and recordings of EEG, body temperature and activity were made for 4 days. Mice were inoculated I.N. at dark onset with 400 PFU (n=13) or 40,000 PFU (n=8) of MuGHV and recordings continued for 30 days. Mice were then injected intraperitoneally (I.P.) at dark onset with vehicle and 24 h control recordings obtained. The mice were injected I.P. with lipopolysaccharide (LPS) and recordings continued for 5 days. Mice housed in the same conditions were inoculated I.N. with vehicle and sacrificed after 4 days or inoculated with 400 PFU or with 40,000 PFU MuGHV and sacrificed 5, 9, or 26 days after inoculation. Brain tissue, blood, spleen, and lung were collected, and stored at -80 °C until assay. RESULTS: Infected mice showed decreases in wheel running activity, core body temperature, food intake and body weight. Mice inoculated with 40,000 PFU of MuGHV had increases in NREM sleep, sleep fragmentation, and wakefulness during the peak of viral replication. Responses of infected mice to LPS were exacerbated. Cytokine concentrations and profiles in brain and the periphery were altered during infection. The alterations in cytokine profiles differed in a complex manner depending on dose of MuGHV. Based upon reductions in wheel running, these results indicate that mice become chronically fatigued during infection with MuGHV. Chronic infection is associated with long-term changes in thermoregulatory mechanisms and the ability of the immune system to respond normally to subsequent challenge. Virus-induced alterations in central cytokine profiles with respect to those in the periphery suggest potential mechanisms that may lead to fatigue. These studies demonstrate the utility of MuGHV as a model for post-viral fatigue infection.