Sleep and fatigue in mice infected with murine gammaherpesvirus 68

Olivadoti MD, Weinberg JB, Toth LA, Opp MR.:

Neuroscience Graduate Program, University of Michigan.
Abstract
Fatigue, a common symptom of many acute and chronic medical conditions, reduces both quality of life and workplace productivity and can be disabling. However, the pathophysiologic mechanisms that underlie fatigue can be difficult to study in human populations due to the patient heterogeneity, the variety of underlying causes and potential triggering events, and inability to collect samples that may be essential to elucidation of mechanisms (e.g., brain).

Although the etiology of chronic fatigue syndrome (CFS) remains elusive, some studies have implicated viral infections, including Epstein-Barr virus (EBV), a human gammaherpesvirus, as a potential factor in the pathogenesis of CFS.

Murine gammaherpesvirus 68 (γHV68) is a mouse pathogen that shares many similarities with human γHVs, including EBV.

In this study, we use γHV68-infected C57BL/6J mice as a model system for studying the impact of chronic viral infection on sleep-wake behavior, activity patterns, and body temperature profiles. Our data show that γHV68 alters sleep, activity, and temperature in a manner suggestive of fatigue. In mice infected with the highest dose used in this study (40,000 plaque forming units), food intake, body weight, wheel running, body temperature, and sleep were normal until approximately 7 days after infection. These parameters were significantly altered during days 7 through 11, returned to baseline levels at day 12 after infection, and remained within the normal range for the remainder of the 30-day period after inoculation. At that time, both infected and uninfected mice were injected with lipopolysaccahride (LPS), and their responses monitored. Uninfected mice given LPS developed a modest and transient febrile response during the initial light phase (hours 12 through 24) after injection. In contrast, infected mice developed changes in core body temperatures that persisted for at least 5 days.

Infected mice showed an initial hypothermia that lasted for approximately 12 h, followed by a modest fever that persisted for several hours. For the remainder of the 5-day recording period, they showed mild hypothermia during the dark phase.

Running wheel activity of infected mice was reduced for at least 5 days after injection of LPS, but for only 12 h in uninfected mice. Collectively, these observations indicate that1) physiologic and behavioral processes in mice are altered and recover during an early phase of infection, and 2) mice with latentγ V68 infectionhave an exacerbated response to challenge with LPS.

These findings indicate that laboratory mice with γHV68infections may provide a useful model for the study of fatigue and other physiologic and behavioral perturbations that may occur during acute and chronic infection with gammaherpesviruses.