Abstract
To define immune mechanisms that regulate chronic and latent herpesvirus infection, we analyzed the role of interferon gamma (IFN-gamma) during murine cytomegalovirus (MCMV) infection. Lethality studies demonstrated a net protective role for IFN-gamma, independent of IFN-alpha/beta, during acute MCMV infection. Mice lacking the IFN-gamma receptor (IFN-gammaR-/-) developed and maintained striking chronic aortic inflammation. Arteritis was associated with inclusion bodies and MCMV antigen in the aortic media. To understand how lack of IFN-gamma responses could lead to chronic vascular disease, we evaluated the role of IFN-gamma in MCMV latency. MCMV-infected IFN-gammaR-/- mice shed preformed infectious MCMV in spleen, peritoneal exudate cells, and salivary gland for up to 6 mo after infection, whereas the majority of congenic control animals cleared chronic productive infection. However, the IFN-gammaR was not required for establishment of latency. Using an in vitro explant reactivation model, we showed that IFN-gamma reversibly inhibited MCMV reactivation from latency. This was at least partly explained by IFN-gamma- mediated blockade of growth of low levels of MCMV in tissue explants. These in vivo and in vitro data suggest that IFN-gamma regulation of reactivation from latency contributes to control of chronic vascular disease caused by MCMV. These studies are the first to demonstrate that a component of the immune system (IFN-gamma) is necessary to regulate MCMV-associated elastic arteritis and latency in vivo and reactivation of a herpesvirus from latency in vitro. This provides a new model for analysis of the interrelationships among herpesvirus latency, the immune system, and chronic disease of the great vessels.
Highlights
We show that IFN-␥ plays an important role during chronic murine cytomegalovirus (MCMV) infection in vivo and during reactivation in vitro
Since latency can be established in the absence of IFN-␥ responsiveness, we examined the hypothesis that IFN-␥ controls reactivation from MCMV latency
MCMV in multiple tissues in addition to the salivary gland [27]; (b) IFN-␥ is not required for establishment of MCMV latency; (c) IFN-␥ can reversibly block reactivation from latency in an in vitro model; (d) one mechanism by which IFN-␥ might regulate chronic MCMV infection is blockade of the growth of low levels of infectious virus; and (e) one consequence of the absence of IFN-␥ responsiveness is chronic inflammatory disease in the large elastic arteries
Summary
To detect and quantitate MCMV genome, nested PCR detecting sequences of the MCMV immediate early 1 gene were performed on DNA from bone marrow cells as described previously [31]. This nested PCR assay reproducibly detects one copy of target plasmid [31, 37]. The arteritis data (Table 1) were analyzed using a Cox proportional hazards model, comparing the IFN-␥RϪրϪ strain to the 129 control with dose and sex as covariates. The bone marrow results were not statistically analyzed as there were no mice that displayed evidence of the shedding virus in their bone marrow
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