Immunity to Pneumonic Tularemia

摘要：土拉菌是土拉菌病的病原体，可通过多种途径感染人类，包括媒介传播。然而，吸入这种细菌以及由此产生的肺炎土拉菌病是最危险的一种疾病。这是由于潜伏期短（3-5天）、非特异性症状和高死亡率（大于80%）。此外，美国和前苏联都将土拉菌武器化，使其成为一种可行的生物武器。尽管全球范围内对土拉菌进行了80多年的研究，但人们对这种细菌与宿主的动态相互作用知之甚少，尤其是在气溶胶感染之后。

Summary: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) and Pam Small (Special Volunteer, Rocky Mountain Labs) 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 testing the capability of these lipids to interfere with inflammatory responses in vivo. 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 observed 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. We are currently identifying how the bacterium evades this detection and the specific inflammasome components it modulates to accomplish this evasion.