Developing a mouse model to examine the specific impact of IFNa in the pathogenesis of genital tract Chlamydia infection

开发小鼠模型来检查 IFNa 在生殖道衣原体感染发病机制中的具体影响

基本信息

  • 批准号:
    10041346
  • 负责人:
  • 金额:
    $ 6.76万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-08-19 至 2023-07-31
  • 项目状态:
    已结题

项目摘要

Reproductive tract pathology caused by Chlamydia infections is the result of the immune responses to the presence of Chlamydia within the female reproductive tract. Both innate and adaptive immune responses are induced as part of the host defense against infection, and specific cytokines and chemokines play a role in regulating these defense mechanisms. Because our previously published data show that TLR3 deficiency leads to a significant decrease in the synthesis of IFN-β during C. muridarum (Cm) infection in OE cells and mice, we hypothesized that IFN-β was likely not a contributing factor to the increased amount of genital tract pathology seen in the TLR3-deficient mice. We further hypothesized that IFN-β was instead a necessary component of the protective immune response to Cm infection. To test these hypotheses, we infected both wild-type and IFN-β KO mice intravaginally with 105 IFU Cm and our preliminary show that IFN-β KO mice had higher chlamydial loads and suffered more genital tract pathology during Cm infection when compared to WT mice. Our data challenge the paradigm that type-1 IFNs are detrimental in the host response to Chlamydia infection that was established by other investigators using interferon α/β receptor (IFNAR) KO mice. However, one of the exciting outcomes of our in vitro investigations into the mechanisms of the Chlamydia-TLR3 interaction was that TLR3-deficiency leads to an overexpression of several IFNα subtypes. This unexpected finding reveals that TLR3 differentially regulates IFNα and IFN-β, whereby it stimulates the induction of IFN-β during Cm infection in OE cells, while simultaneously down-regulating the expression of IFNα. The over-expression of IFNα during TLR3 deficiency implicates IFNα (and not IFN-β) as a possible contributor to the increased genital tract pathology seen in TLR3-deficient mice and would support the narrative of a type- 1 IFN exacerbating the Chlamydia-caused genital tract pathology reported by others using IFNAR KO mice. The research plan for Specific Aim #1 describes using CRISPR-Cas9 to generate an inbred knock-out mouse strain that is deficient in the gene expression and protein function of IFNα subtypes 2, 4, 12, and 13. Because these four subtypes of IFNα represent the only IFNα subtypes induced during Cm infection of murine genital tract epithelium, this quadruple KO mouse will be an important reagent for us to test the hypothesis that IFNα contributes to reproductive tract pathology during Cm infection both in vitro and in vivo.
由衣原体感染引起的生殖道病理是对衣原体存在的免疫应答的结果。 女性生殖道内的衣原体。先天性和适应性免疫反应都是作为宿主的一部分而被诱导的。 细胞因子和趋化因子在调节这些防御机制中发挥作用。 因为我们以前发表的数据表明,TLR 3缺乏导致IFN-β合成的显着减少, 在C.在OE细胞和小鼠中,我们假设IFN-β可能不是一个促成因素, 在TLR 3缺陷小鼠中观察到的生殖道病理学数量增加。我们进一步假设IFN-β 相反,它是对Cm感染的保护性免疫反应的必要组成部分。为了验证这些假设,我们 用105 IFU Cm阴道内感染野生型和IFN-β KO小鼠,我们的初步结果表明,IFN-β KO小鼠 与WT小鼠相比,在Cm感染期间具有更高的衣原体载量和遭受更多的生殖道病理。 我们的数据挑战了1型干扰素在宿主对衣原体感染的反应中是有害的这一范式, 由其他研究者使用干扰素α/β受体(IFNAR)KO小鼠建立。然而,令人兴奋的结果之一是, 我们对衣原体-TLR 3相互作用机制的体外研究表明,TLR 3缺乏导致 几种IFNα亚型的过表达。这一出乎意料的发现揭示了TLR 3对IFNα和IFN β的调节差异。 IFN-β,从而在OE细胞中的Cm感染期间刺激IFN-β的诱导,同时下调IFN-β的表达。 IFNα的表达。在TLR 3缺乏期间IFNα的过度表达暗示IFNα(而不是IFN-β)可能是TLR 3缺乏的一个原因。 在TLR 3缺陷小鼠中观察到的生殖道病理学增加的贡献者,并将支持一种类型的叙述, 1 IFN加剧衣原体引起的生殖道病理学,其他人使用IFNAR KO小鼠报道。研究 Specific Aim #1的计划描述了使用CRISPR-Cas9来产生近交系敲除小鼠品系,该近交系敲除小鼠品系在CRISPR-Cas9中是缺陷的。 IFNα亚型2、4、12和13的基因表达和蛋白质功能。因为这四种IFNα亚型代表了 只有在小鼠生殖道上皮的Cm感染期间诱导IFNα亚型,这种四重KO小鼠将是一种 为我们检验α干扰素参与生殖道病理的假说提供了重要的试剂 无论是在体外还是在体内。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

WILBERT A DERBIGNY其他文献

WILBERT A DERBIGNY的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('WILBERT A DERBIGNY', 18)}}的其他基金

Investigating whether chlamydia trachomatis can increase the infectivity of HPV during genital tract infections
研究沙眼衣原体是否可以增加生殖道感染期间 HPV 的传染性
  • 批准号:
    10648156
  • 财政年份:
    2023
  • 资助金额:
    $ 6.76万
  • 项目类别:
The role of TLR3 signaling in Chlamydia caused urogenital pathology
TLR3信号在衣原体引起的泌尿生殖病理中的作用
  • 批准号:
    8761903
  • 财政年份:
    2014
  • 资助金额:
    $ 6.76万
  • 项目类别:
The role of TLR3 signaling in Chlamydia caused urogenital pathology
TLR3信号在衣原体引起的泌尿生殖病理中的作用
  • 批准号:
    8916541
  • 财政年份:
    2014
  • 资助金额:
    $ 6.76万
  • 项目类别:
The role of TLR3 signaling in Chlamydia caused urogenital pathology
TLR3信号在衣原体引起的泌尿生殖病理中的作用
  • 批准号:
    9117379
  • 财政年份:
    2014
  • 资助金额:
    $ 6.76万
  • 项目类别:
The role of TLR3 signaling in Chlamydia caused urogenital pathology
TLR3信号在衣原体引起的泌尿生殖病理中的作用
  • 批准号:
    9327861
  • 财政年份:
    2014
  • 资助金额:
    $ 6.76万
  • 项目类别:
Chlamydia-infected Epithelial Cell Secretion of Immunoregulatory Cytokines
衣原体感染的上皮细胞分泌免疫调节细胞因子
  • 批准号:
    7470141
  • 财政年份:
    2007
  • 资助金额:
    $ 6.76万
  • 项目类别:
Chlamydia-infected Epithelial Cell Secretion of Immunoregulatory Cytokines
衣原体感染的上皮细胞分泌免疫调节细胞因子
  • 批准号:
    7317231
  • 财政年份:
    2007
  • 资助金额:
    $ 6.76万
  • 项目类别:

相似海外基金

The earliest exploration of land by animals: from trace fossils to numerical analyses
动物对陆地的最早探索:从痕迹化石到数值分析
  • 批准号:
    EP/Z000920/1
  • 财政年份:
    2025
  • 资助金额:
    $ 6.76万
  • 项目类别:
    Fellowship
Animals and geopolitics in South Asian borderlands
南亚边境地区的动物和地缘政治
  • 批准号:
    FT230100276
  • 财政年份:
    2024
  • 资助金额:
    $ 6.76万
  • 项目类别:
    ARC Future Fellowships
The function of the RNA methylome in animals
RNA甲基化组在动物中的功能
  • 批准号:
    MR/X024261/1
  • 财政年份:
    2024
  • 资助金额:
    $ 6.76万
  • 项目类别:
    Fellowship
Ecological and phylogenomic insights into infectious diseases in animals
对动物传染病的生态学和系统发育学见解
  • 批准号:
    DE240100388
  • 财政年份:
    2024
  • 资助金额:
    $ 6.76万
  • 项目类别:
    Discovery Early Career Researcher Award
Zootropolis: Multi-species archaeological, ecological and historical approaches to animals in Medieval urban Scotland
Zootropolis:苏格兰中世纪城市动物的多物种考古、生态和历史方法
  • 批准号:
    2889694
  • 财政年份:
    2023
  • 资助金额:
    $ 6.76万
  • 项目类别:
    Studentship
Using novel modelling approaches to investigate the evolution of symmetry in early animals.
使用新颖的建模方法来研究早期动物的对称性进化。
  • 批准号:
    2842926
  • 财政年份:
    2023
  • 资助金额:
    $ 6.76万
  • 项目类别:
    Studentship
Study of human late fetal lung tissue and 3D in vitro organoids to replace and reduce animals in lung developmental research
研究人类晚期胎儿肺组织和 3D 体外类器官在肺发育研究中替代和减少动物
  • 批准号:
    NC/X001644/1
  • 财政年份:
    2023
  • 资助金额:
    $ 6.76万
  • 项目类别:
    Training Grant
RUI: Unilateral Lasing in Underwater Animals
RUI:水下动物的单侧激光攻击
  • 批准号:
    2337595
  • 财政年份:
    2023
  • 资助金额:
    $ 6.76万
  • 项目类别:
    Continuing Grant
RUI:OSIB:The effects of high disease risk on uninfected animals
RUI:OSIB:高疾病风险对未感染动物的影响
  • 批准号:
    2232190
  • 财政年份:
    2023
  • 资助金额:
    $ 6.76万
  • 项目类别:
    Continuing Grant
A method for identifying taxonomy of plants and animals in metagenomic samples
一种识别宏基因组样本中植物和动物分类的方法
  • 批准号:
    23K17514
  • 财政年份:
    2023
  • 资助金额:
    $ 6.76万
  • 项目类别:
    Grant-in-Aid for Challenging Research (Exploratory)
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了