Environmental perturbation, inflammation and behavior in healthy and virus-infected mice.

The development of so-called "sickness behaviors" (e.g., anorexia, anhedonia, reduced social interaction, fatigue) during infectious and inflammatory disease has been linked to facets of the immune response. Such problems can be particularly troublesome during chronic latent infection, as the host immune system must employ continual vigilance to maintain viral latency. Epstein-Barr virus (EBV) is a ubiquitous human gamma-herpesvirus that causes acute disease and establishes life-long latency in people. Murine gammaherpesvirus (MuGHV) is a natural pathogen of wild rodents that provides an experimental model for studying the pathophysiology of an EBV-like gamma-herpesvirus in mice. To evaluate this model with regard to sickness behavior and its exacerbation during a chronic latent viral disease, we exposed uninfected and MuGHV-infected C57BL/6J and BALB/cByJ mice to novel and potentially stressful environmental perturbations and measured the impact of these challenges on behavior and markers of inflammation. The data indicate that exposure of mice to environmental perturbations during the normal somnolent phase is associated with reduced activity during the subsequent active phase, despite an intervening rest period. Effects on inflammatory mediators were complex due to independent and interactive effects of infection status, mouse strain, and exposure to stressful environment. However, GCSF and MCP1 were consistently elevated in lung both immediately after and 12h after exposure to a "dirty" cage containing the resident mouse (DCR); this increase occurred in both C57BL/6J and BALB/cByJ mice and was independent of infection status. At 12h after DCR, IL1β and IP10 were also consistently elevated in lung. In response to DCR, BALB/cByJ mice showed a greater number of significant cytokine effects than did C57BL/6J mice. With regard to infection status, IP10 was consistently elevated in lung at both time points regardless of mouse strain or DCR exposure. Several analytes were affected by mouse strain in serum or lung at one or both time points, with most strain differences present in serum at E18. Taken together, the data show that exposure of mice to environmental perturbations is associated with systemic inflammation that is in part independent of genetic background or latent MuGHV infection and with reduced activity that could represent fatigue, depression, or other facets of sickness behavior.