Human cytomegalovirus (CMV), like other beta herpes viruses, has the ability to become latent following primary infection. CMV can later reactivate from latency, and following reactivation is a well known pathogen in immmunosuppressed transplant and AIDS patients. We have recently demonstrated that critically ill surgical patients can also reactivate latent CMV, and that it appears to be a pulmonary pathogen in these patients, with worsened morbidity and possibly mortality. Unfortunately, the trigger for this reactivation remains unknown. A number of stimuli have been related to reactivation, including immunosuppression, allogeneic stimulation from transplant, cytokine stimulation, and bacterial sepsis. Using an animal model, we have recently demonstrated that intra-abdominal bacterial sepsis can cause distant reactivation of latent CMV in lungs of immunocompetent mice. Further, we have shown that this reactivation occurs in multiple organs, suggesting the possible involvement of a circulating mediator. Several inflammatory mediators released during sepsis, including endotoxin and tumor necrosis factor, have been shown to be stimulatory to CMV replication, and thus might be responsible for reactivation in this model. In addition, these mediators are known to cause significant local end organ inflammation, and our preliminary data suggests that this local inflammation may contribute to reactivation of CMV from latency. Finally, our preliminary data also suggests that reactivation of CMV from latency also causes pathology in the immunocompetent host. This proposal, therefore, will focus on determining the mechanisms by which bacterial sepsis induces reactivation of latent CMV in lungs of immunocompetent hosts. Based upon our preliminary data, we will test the hypothesis that inflammatory mediators induced by sepsis, acting either systemically or locally, stimulate CMV reactivation from latency.
In Specific Aim I, we will evaluate the role of systemic and local inflammation in reactivation of latent CMV.
Specific Aim II will investigate the role of nuclear factor kappa B activation in sepsis-triggered reactivation.
In Specific Aim III, we will further investigate the injurious effects of pulmonary CMV reactivation. The long-term goals of our laboratory are to elucidate the critical cellular and molecular factors mediating CMV reactivation from latency in critically ill surgical patients, and to utilize these data in directing therapy to ameliorate CMV disease.
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