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.

Francisella tularensis is the causative agent of the human disease tularemia. F. tularensis infects a variety of cells, including macrophages, in order to cause pathogenicity. As few as 10 inhaled microorganisms cause a lethal infection by over-activating the host’s own inflammatory response. Differences in the intensity of the inflammatory response exist between the sexes which leads to differences in sensitivity to autoimmune and infectious disease. Males tend to be more susceptible to infectious diseases whereas females tend to be more susceptible to autoimmune diseases. However, our preliminary data unexpectedly demonstrated that female mice were more susceptible to F. tularensis--mediated disease than male mice. We hypothesized that female macrophages respond to F. tularensis infection by generating a more intense inflammatory response which makes females more susceptible to F. tularensis. Indeed, female mice infected with F. tularensis generate significantly more inflammatory M1 macrophages compared to male mice. Furthermore, naïve M1 and M2 macrophages were infected in vitro to directly compare cellular responses between male and female mice. On a per cell basis, M1 macrophages from female mice generated a more robust inflammatory response compared with M1 macrophages from male mice. This suggests that M1 macrophages from females respond more strongly to infection resulting in the heightened inflammatory response.

Francisella tularensisis the causative agent of the human disease tularemia. F. tularensisinfects a variety of cells, including macrophages, in order to cause pathogenicity. As few as 10 inhaled microorganisms cause a lethal infection by over-activating the host’s own inflammatory response. Differences in the intensity of the inflammatory response exist between the sexes which leads to differences in sensitivity to autoimmune and infectious disease. Males tend to be more susceptible to infectious diseases whereas females tend to be more susceptible to autoimmune diseases. However, our preliminary data unexpectedly demonstrated that female mice were more susceptible to F. tularensis-mediated disease than male mice. We hypothesize that the elevated inflammatory state of females may make them more susceptible to F. tularensis disease and that the M1 and M2 macrophage subsets may determine this differential inflammatory response. Naïve M1 and M2 macrophages will be purified from male and female mice and infected in vitro to directly compare cellular responses between male and female mice. In parallel, M0 macrophages will be differentiated in vitro prior to infection for similar comparison.