Francisella tularensis Infection of Mice as a Model of Sepsis.

Sepsis results from the dysregulated immune response to infection. While the stimulator and progression of the septic response is poorly understood, the systemic production of a storm of cytokines is common in all etiologies of sepsis. While the complexity of this uncontrolled cascade is difficult to replicate using single molecule agonist, for example, lipopolysaccharide (LPS), several whole organism models can stimulate this cytokine storm. Herein, we detail protocols developed to trigger and analyze the systemic septic response in mouse models using the bacterium Francisella tularensis.

Obesity Exacerbates the Cytokine Storm Elicited by Francisella tularensis Infection of Females and Is Associated with Increased Mortality.

Infection with Francisella tularensis, the causative agent of the human disease tularemia, results in the overproduction of inflammatory cytokines, termed the cytokine storm. Excess metabolic byproducts of obesity accumulate in obese individuals and activate the same inflammatory signaling pathways as F. tularensis infection. In addition, elevated levels of leptin in obese individuals also increase inflammation. Since leptin is produced by adipocytes, we hypothesized that increased fat of obese females may make them more susceptible to F. tularensis infection compared with lean individuals. Lean and obese female mice were infected with F. tularensis and the immunopathology and susceptibility monitored. Plasma and tissue cytokines were analyzed by multiplex ELISA and real-time RT-PCR, respectively. Obese mice were more sensitive to infection, developing a more intense cytokine storm, which was associated with increased death of obese mice compared with lean mice. This enhanced inflammatory response correlated with in vitro bacteria-infected macrophage cultures where addition of leptin led to increased production of inflammatory cytokines. We conclude that increased basal leptin expression in obese individuals causes a persistent low-level inflammatory response making them more susceptible to F. tularensis infection and heightening the generation of the immunopathological cytokine storm.