Modulation of Human Cells by Virulent Francisella tularensis

摘要：图拉氏方济氏菌是图拉热病的病原体，可通过多种途径感染人类，包括通过媒介传播。然而，吸入细菌和由此导致的肺炎图拉热症是最危险的疾病形式。这是由于未经治疗的患者的潜伏期短(3-5天)、非特异性症状以及高死亡率(大于80%)。此外，美国和前苏联都已将其武器化，使其成为用作生物武器的可行候选者。尽管世界各地对图拉氏杆菌进行了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，特别是在气溶胶感染之后。 我的实验室最近发现，与小鼠细胞类似，人类树突状细胞对图拉氏杆菌感染非常敏感，但不能产生促炎细胞因子或经历成熟。此外，毒力较强的图拉氏杆菌能有效干扰人类DC对二次刺激的反应能力。人树突状细胞在感染图拉氏丝虫后反应性差的一种解释是这些细胞缺乏CD14。CD14似乎在细胞暴露于图拉氏丝虫后引发炎症的过程中起着关键作用。缺乏CD14的细胞仍然容易感染，但不能产生促炎细胞因子。此外，这些细胞对其他微生物成分的进一步刺激变得难以接受。图拉氏丝虫及其组分与CD14相互作用的具体作用和机制目前正在实验室进行研究。 图拉氏丝孢子虫通过多种途径负性调节人树突状细胞。例如，如果细胞外细菌的复制受到限制，人类树突状细胞产生肿瘤坏死因子-α的能力就会恢复，以应对其他微生物的刺激。然而，没有观察到类似的IL-12产生的恢复。我们目前正在剖析图拉氏杆菌毒力株调控人类树突状细胞宿主反应的具体途径和分子机制。除了帮助开发新的疫苗和治疗方法外，识别能够负调控特定宿主途径(同时保持其他途径不变)的细菌产品可能为针对癌症和自身免疫性疾病的治疗提供新的靶点。

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%) in untreated individuals. 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. My laboratory recently shown that, similarly to murine cells, human dendritic cells are acutely susceptible to infection with F. tularensis, but fail to produce pro-inflammatory cytokines or undergo maturation. Further, virulent F. tularensis actively interferes with the ability of human DC to respond to secondary stimuli. One explanation for the poor responsiveness of human DC following infection with F. tularensis is that these cells lack CD14. CD14 appears to be a critical player in the elicitation of inflammation following exposure of cells to F. tularensis. Cells that lack CD14 are still susceptible to infection, but fail to produce pro-inflammatory cytokines. Furthermore, these cells become refractory to further stimulation by other microbial components. The specific role and the mechanism in which F. tularensis and its components interacts with CD14 is currently under investigation in the laboratory. F. tularensis negatively regulates human dendritic cells through multiple pathways. For example, if the replication of extracellular bacteria is restricted, the ability of human dendritic cells to produce TNF-alpha in response to other microbial stimuli is restored. However, a similar restoration of IL-12 production is not observed. We are currently dissecting the specific pathways and molecular mechanisms by which virulent F. tularensis modulates host responses in human dendritic cells. In addition to aiding in the development of novel vaccines and therapeutics, identification of bacterial products capable of negatively regulating specific host pathways (while leaving others intact) may provide new targets for therapeutics directed against cancer and autoimmune diseases.