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Abstract: TH-PO976

CMV Modifies Disease Progression in a Mouse Model of Sepsis

Session Information

Category: Pathology and Lab Medicine

  • 1501 Pathology and Lab Medicine: Basic

Authors

  • Nash, William, University of Virginia, Charlottesville, Virginia, United States
  • Brown, Michael G., University of Virginia, Charlottesville, Virginia, United States
  • Swaminathan, Sundararaman, University of Virginia, Charlottesville, Virginia, United States
Background

Sepsis is the leading cause of death in hospitals and accounts for around 250,000 deaths in the U.S. anually. Despite its prominence as a global health concern, relatively little is understood about the mechanisms associated with survival or mortality. This is, in part, due to the failure of promising data from animal models to translate into measurable benefits during clinical trials. Hence, improving trial and animal model design are two main focuses in the field. We are approaching this issue by considering the effect of a history of infection on sepsis progression. A major difference between mice and human patients is their exposure to pathogens. Nearly all patients will have a latent infection of some kind and understanding how this may influence the septic syndrome is an important healthcare priority.

Methods

Cecal contents were collected from B6-background mice and processed into a working-stock slurry. Sepsis was induced in experimental mice via i.p. injection of slurry stock induce to life-threatening sepsis. Prior to sepsis, some experimental mice were injected with MCMV and allowed to progress to latency (60+ days). Septic mice were monitored frequently and survival, body weight, and clinical score were recorded. Upon reaching an endpoint, serum and tissue were collected for further analysis.

Results

When CMV-naive and CMV-latent male mice were given body weight-adjusted doses of cecal slurry, all CMV-naive mice succumbed within 2 days while all CMV-latent mice survived out to 13 days (experimental endpoint). Upon further investigation, CMV-latent mice were found to have greater preservation of MHC class II on splenic dendritic cells which correlated with a greater representation of splenic CD3+ cells while CD19+ cell representation was unchanged. Analysis of mice treated with an LD50 dose of slurry for 48 hours revealed that CMV-latent mice also trended toward lesser clinical scores, controlled body weight loss, and higher serum levels of IFNγ, IL-12p70, and IL-1β. BUN levels were elevated in the serum of all mice at 48 hours, but we did not detect any CMV-specific alterations.

Conclusion

The data suggest that CMV is modifying the early progression of sepsis and favoring less severe disease. These effects appear to stem from experience of the immune system leading to a better regulated inflammatory response and preservation of specific lymphocyte populations.

Funding

  • NIDDK Support