Modulation of hepatic PPAR expression during Ft LVS LPS-induced protection from Francisella tularensis LVS infection

To further investigate the molecular mechanisms that underlie Ft LVS LPS-mediated protection, we profiled global hepatic gene expression following Ft LVS LPS or saline pre-treatment and subsequent Ft LVS challenge using Affymetrix arrays.A large number of genes (> 3,000) were differentially expressed at 48 hours post-infection. The degree of modulation of inflammatory genes by infection was clearly attenuated by pre-treatment with Ft LVS LPS in the surviving mice. However, Ft LVS LPS alone had a subtle effect on the gene expression profile of the uninfected mice. By employing gene set enrichment analysis, we discovered significant up-regulation of the fatty acid metabolism pathway, which is regulated by peroxisome proliferator activated receptors (PPARs).We hypothesize that the LPS-induced blunting of pro-inflammatory response in mouse is, in part, mediated by PPARs (α and γ).Tularemia is caused by the Gram-negative, non-motile, intracellular coccobacillus, Francisella tularensis (Ft), so named after Tulare county of California where the disease was initially identified [1]. Rodents, along with rabbits and hares, are the chief hosts of the bacterium. It is transmitted to humans mostly by insect bites, handling of animal carcasses, and ingestion or inhalation. Symptoms of tularemia typically appear 3 to 5 days after initial contact with the pathogen and include sudden fever, chills, headaches, diarrhea, muscle aches, joint pain, dry cough and progressive weakness; however, the symptoms and the severity of illness, are highly dependent upon the dose and route of inoculation [2]. The number of cases of tularemia has steadily declined in the United States since 1950; between 1990 and 2000, only 1,368 cases of tularemia were reported to the Centers for Disease Control and Prevention (CDC) with an annual average of approximately 120 cases until 2003 [3]. The CDC has classified Ft as a Category A agent due to its low infectious dose, easy dissemination by the aerosol route