Development of a Rationally Attenuated Live Vaccine for Francisella tularensis

土拉弗朗西斯菌合理减毒活疫苗的研制

基本信息

  • 批准号:
    8650788
  • 负责人:
  • 金额:
    $ 23.03万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2013
  • 资助国家:
    美国
  • 起止时间:
    2013-04-10 至 2016-03-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Francisella tularensis (Ft) is a Gram negative, intracellular (macrophage-tropic) bacterium, and the etiologic agent of tularemia. Ft is classified as a Category A agent because it may can be contracted with low inocula by the respiratory route and causes rapid morbidity and mortality if untreated both mice and humans. Ft Live Vaccine Strain (LVS), a type B strain derived from Ft subsp. holarctica, is attenuated for man, but causes a tularemia-like disease in mice when administered intranasally or intraperitoneally. Although Ft LVS was shown to reduce the incidence of laboratory-acquired respiratory tularemia, it is not licensed in the USA because the molecular basis for its attenuation has not been fully elucidated, the strain exhibits phenotypic inconsistencies, and Ft LVS immunization fails to provide complete protection against some subspecies of Ft. Therefore, additional prophylactic products and/or attenuated vaccine strains must be developed for use against possible bioterrorism threats. Our recently published results show that insertional inactivation of the lpxF gene in F. novicida (Fn) resulted in an attenuated strain with an altered lipopolysaccharide (LPS) structure that protected immunized mice against >25,000 LD50 challenge with wild-type (WT) Fn. We now show that a similar mutation in Ft LVS resulted in the same structural modification to the lipid A and was avirulent at >106 LD50 after subcutaneous infection of C57BL/6 and BALB/c mice. The goal of this revised R21 proposal is to develop live, rationally attenuated Ft vaccines based on unmarked deletion of lpxF in both Ft LVS (Type B) and Ft Schu S4 (Type A) strains. After engineering an unmarked lpxF deletion in these two strains, we will confirm the structure of the lipid A from each mutant by mass spectroscopy, and confirm that each mutant is, indeed, attenuated in mice. Additionally, we will test their capacity to protect WT, IFN-r-/-, and TLR2-/- mice against homologous and heterologous challenge. Finally, we will test for the capacity of each mutant strain to induce macrophage gene expression associated with "classically activated" (microbicidal) vs. "alternatively activated" (shown previously to facilitate intracytosolic replication) macrophages and for the ability to replicate intracellularly in vitro. At the completion of this study, we expect to have developed a rationally attenuated vaccine candidate that will protect against multiple Ft Type A and Type B Francisella strains.
描述(申请人提供):图拉氏方济氏菌(Ft)是一种革兰氏阴性、细胞内(嗜巨噬细胞)细菌,是图拉热症的病原体。《金融时报》被分类 作为A类制剂,因为它可能通过呼吸道途径感染低接种量,如果不对小鼠和人类进行治疗,会导致迅速的发病率和死亡率。FT活疫苗株(LVS)是一株来源于Ft亚种的B型毒株。Holarctica对人类是减毒的,但在小鼠鼻腔或腹膜内给药时会引起一种类似图拉热病的疾病。尽管Ft LVS被证明可以降低实验室获得的呼吸性兔热病的发病率,但由于其减弱的分子基础尚未完全阐明,毒株表现出表型不一致,以及Ft LVS免疫未能对Ft的某些亚种提供完全保护,Ft LVS在美国尚未获得许可。因此,必须开发更多的预防产品和/或减毒疫苗毒株,以应对可能的生物恐怖主义威胁。我们最近发表的结果表明,插入失活 Novicida(FN)中的lpxF基因导致了一种具有改变的脂多糖(LPS)结构的减毒株,以保护免疫小鼠免受野生型(WT)Fn的>25,000 LD50攻击。我们现在证明,在C57BL/6和BALB/c小鼠皮下感染后,Ft LVS上的一个类似的突变导致与脂质A相同的结构修饰,并且在>106LD50处是无毒的。这项修订的R21提案的目标是开发基于在Ft LV(B型)和Ft Schu S4(A型)毒株中未标记的lpxF缺失的合理减毒的Ft活疫苗。在这两个菌株中设计了一个未标记的lpxF缺失后,我们将通过质谱学确认每个突变体的脂类A的结构,并确认每个突变体在小鼠身上确实是弱化的。此外,我们将测试它们保护WT、干扰素-r-/-和TLR2-/-小鼠免受同源和异源挑战的能力。最后,我们将测试每个突变株诱导巨噬细胞基因表达的能力,这些基因与“经典激活”(杀微生物活性)和“交替激活”(先前显示为促进胞浆内复制)巨噬细胞相关,以及在体外细胞内复制的能力。在这项研究完成时,我们预计已经开发出一种合理减毒的候选疫苗,将对多种Ft A型和B型弗朗西斯氏菌菌株具有保护作用。

项目成果

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Robert K Ernst其他文献

Robert K Ernst的其他文献

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{{ truncateString('Robert K Ernst', 18)}}的其他基金

Microbial adaptation of Pseudomonas lipid A structure in CF airway disease progress
假单胞菌脂质 A 结构在 CF 气道疾病进展中的微生物适应
  • 批准号:
    10722599
  • 财政年份:
    2023
  • 资助金额:
    $ 23.03万
  • 项目类别:
Mid-Atlantic Microbial Pathogenesis Meeting 2022
2022 年大西洋中部微生物发病机制会议
  • 批准号:
    10504721
  • 财政年份:
    2022
  • 资助金额:
    $ 23.03万
  • 项目类别:
MS Diagnostic Bacterial Identification Library
MS 诊断细菌鉴定库
  • 批准号:
    10116273
  • 财政年份:
    2020
  • 资助金额:
    $ 23.03万
  • 项目类别:
MS Diagnostic Bacterial Identification Library
MS 诊断细菌鉴定库
  • 批准号:
    10356152
  • 财政年份:
    2020
  • 资助金额:
    $ 23.03万
  • 项目类别:
MS Diagnostic Bacterial Identification Library
MS 诊断细菌鉴定库
  • 批准号:
    10570981
  • 财政年份:
    2020
  • 资助金额:
    $ 23.03万
  • 项目类别:
Protection Against Gram-Negative Sepsis Conferred by Lipid A-Based Structural Variants
基于脂质 A 的结构变体可预防革兰氏阴性脓毒症
  • 批准号:
    9753900
  • 财政年份:
    2016
  • 资助金额:
    $ 23.03万
  • 项目类别:
MS diagnostic bacterial identification library
MS诊断细菌鉴定文库
  • 批准号:
    8722128
  • 财政年份:
    2014
  • 资助金额:
    $ 23.03万
  • 项目类别:
Development of a Rationally Attenuated Live Vaccine for Francisella tularensis
土拉弗朗西斯菌合理减毒活疫苗的研制
  • 批准号:
    8511015
  • 财政年份:
    2013
  • 资助金额:
    $ 23.03万
  • 项目类别:
Immunotherapeutic Potential of Modified Lipooligosaccharides and Lipid A's
修饰脂寡糖和脂质 A 的免疫治疗潜力
  • 批准号:
    8675799
  • 财政年份:
    2013
  • 资助金额:
    $ 23.03万
  • 项目类别:
Immunotherapeutic Potential of Modified Lipooligosaccharides and Lipid A's
修饰脂寡糖和脂质 A 的免疫治疗潜力
  • 批准号:
    8584054
  • 财政年份:
    2013
  • 资助金额:
    $ 23.03万
  • 项目类别:

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