Repression of inflammasome by Francisella tularensis

图拉氏方济氏菌(Francisella tularsis，Ft)是人类致命疾病图拉热症的病原体，长期以来一直被开发出来 作为生物武器，因为它有能力导致严重的疾病。《金融时报》现在被归类为A类精选 美国疾病控制与预防中心基于其可能用作生物恐怖制剂的证据。FT是一种细胞内病原体。在其 在复制周期中，Ft从吞噬小体逃逸并在几种细胞类型的胞浆中复制；因此， 胞浆模式识别受体，特别是NLR和炎症体在先天免疫中的作用 对Ft的打击具有重要意义。炎性小体是一种胞浆多蛋白复合体，可激活 Caspase1产生促炎细胞因子IL-1β和IL-18是招募和激活 其他免疫细胞促进细菌清除。人们对炎性小体的作用知之甚少。 在对强毒Ft菌株的寄主防御中。我们的总体假设是对炎性小体的主动抑制 是Ft细胞内生存所必需的。在我们的两年中进行的研究的结果 之前的R15融资周期已经证明，Ft编码的因子抑制了AIM2和Nlrp3 炎性小体；AIM2和Nlrp3对于疫苗诱导的保护性免疫反应都是必不可少的； Nlrp3在Ft感染的巨噬细胞和小鼠中发挥非炎症体依赖的有害作用。这个 当前提案的科学前提建立在以下两个悬而未决的问题上 研究：(1)Ft抑制AIM2炎症小体的总体后果是什么 先天免疫反应的发展？(2)Nlrp3如何对宿主产生不利影响 在Ft感染之后？在具体目标1中，我们将研究AIM2调节 宿主对Ft感染的免疫力。我们将调查压制AIM2的后果 炎症体对弗朗西斯杆菌感染过程中先天免疫反应整体发展的影响。这个 非炎症体非依赖性NLRs的作用，尤其是作为炎症的负面调节，已经到了 近几年走在了前列。我们的初步研究表明，Nlrp3增加了小鼠对 抑制Ft感染的小鼠和巨噬细胞产生促炎细胞因子。在……里面 具体目标2，我们将研究Nlrp3调节宿主免疫和 通过抑制宿主对弗朗西塞氏菌的先天免疫反应起到有害的作用。这些 建议的研究是新颖的，将加强我们对Ft的独特致病机制的理解， 这对于开发有效的图拉热病治疗方法和疫苗至关重要。

Francisella tularensis (Ft), the causative agent of fatal human disease tularemia has long been developed as a biological weapon due to its ability to cause severe illness. Ft is now classified as a category A select agent by the CDC based on its possible use as a bioterror agent. Ft is an intracellular pathogen. During its replication cycle, Ft escapes from the phagosome and replicates within the cytosol of several cell types; thus, the role of cytosolic pattern recognition receptors, especially the NLRs and inflammasome in innate immunity against Ft assumes great importance. The inflammasome is a cytosolic multi-protein complex that activates caspase1 to produce pro-inflammatory cytokines IL-1β and IL-18 required for recruitment and activation of other immune cells to promote bacterial clearance. Very little is known regarding the role of the inflammasome in host defense against virulent Ft strains. Our overall hypothesis is that active repression of the inflammasome is essentially required for intracellular survival of Ft. Results from the studies conducted during our two previous R15 funding cycles have demonstrated that Ft encoded factors suppress Aim2 and Nlrp3 inflammasomes; both the Aim2 and Nlrp3 are dispensable for vaccine-induced protective immune responses; and Nlrp3 plays an inflammasome-independent detrimental role in Ft infected macrophages and mice. The scientific premise of the current proposal is built upon two unanswered questions emanating from these studies: (1) what are the consequences of suppression of the Aim2 inflammasome by Ft on the overall development of innate immune responses? (2) How does Nlrp3 exert its detrimental effects on the host following Ft infection? In specific aim 1, we will investigate the mechanisms through which Aim2 regulates the host’s immunity to Ft infection. We will investigate the consequences of suppression of the Aim2 inflammasome on the overall development of innate immune responses during Francisella infection. The inflammasome-independent roles of NLRs, especially as negative regulators of inflammation, have come to the forefront in recent years. Our preliminary studies demonstrate that Nlrp3 increases the susceptibility of mice and suppresses the production of pro-inflammatory cytokines in mice and macrophages infected with Ft. In specific aim 2, we will investigate the mechanisms through which Nlrp3 regulates the host’s immunity and plays a detrimental role by dampening the host’s innate immune responses against Francisella. These proposed studies are novel and will enhance our understanding of the unique pathogenic mechanisms of Ft, which are essential for the development of effective therapeutics and vaccines against tularemia.