Francisella tularensis, the causative agent for tularemia, can infect humans by a number of routes, including vector-borne transmission. However, it is inhalation of the bacterium, and the resulting pneumonic tularemia, that represents the most dangerous form of disease. This is due to the short incubation time (3-5 days), non-specific symptoms, and a high mortality rate (greater than 80%). Furthermore, F. tularensis has been weaponized by both the United States and the former Soviet Union making it a viable candidate for use as a biological weapon. Despite over 80 years of research on F. tularensis around the world, very little is understood about the dynamic interaction of this bacterium with the host, especially following aerosol infection. In the last several years my laboratory has provided abundant evidence that one of the primary mechanisms by which F. tularensis successfully infects and replicates in the host is via active interference with development of inflammatory responses in the lungs. A major hurdle in studying virulent F. tularensis in vivo is that animals require euthanasia within a few days of infection. This does not allow reliable assessment of the interaction of the bacterium with the host immune system. To overcome this obstacle we developed a model using antibiotics in which we provoke slow clearance of F. tularensis and survival among infected animals. This model has both identified host requirements for survival of tularemia and, importantly, demonstrated that many of these requirements are different than those observed using attenuated strains. Specifically, we have shown that both IL-12p40 and IL-12p35 are essential in defense against F. tularensis infection. We are now utilizing this model to identify host factors that contribute to the exacerbation of F. tularensis infection. We have also identified components of the bacterium that contribute to dampening inflammatory responses in the host using in vitro systems. In collaboration with our colleagues, Richard Lee (St. Jude Childrens Hospital) we have shown that lipids isolated from virulent F. tularensis, but not attenuated strains, fail to stimulate inflammatory responses and (importantly) interfere with the ability of host cells to respond to unrelated stimuli. We are currently identifying the specific host cell pathways modualted by tehse lipids that inhibit production of IL-12 in vivo adn in vitro. Data gathered from these studies will expand our understanding of tularemia and enable development of novel therapeutics and vaccines. Additionally, these lipids may be adapted for use as potent anti-inflammatory agents for use against unrelated conditions such as allergic asthma. Finally, we established that virulent F. tularensis stimulates rapid production of IFN-beta as a mechanism to selectively inhibit production of IL-12 in human dendritic cells. The findings were recently published in the Journal of Immunology. Further, unlike infection with attenuated strains IFN-b did not aid in resolution of infection nor did the presence of this host cytokine contribute to activation of the inflammasome. We are extended these observations to our mouse model and have shown that F. tularensis evades activation of the inflammasome but does not inhibit its assembly. Rather the bacterium specifically targets mRNA for pro-inflammatory cytokines (via destabilization) that depend on the inflammasome for activation. We are currently identifying the specific mechanism by which F. tularensis destabilizes host mRNA to inhibit production of inflamamtory cytokines.
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