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
- 来源:
- 关键词:Animal ModelAnimalsAntibioticsBacteriaCRISPR/Cas technologyCase StudyCell physiologyChlamydiaChlamydia InfectionsChlamydia muridarumChlamydia trachomatisChronicChronic DiseaseClinicalClustered Regularly Interspaced Short Palindromic RepeatsCommunitiesComplexDataDefense MechanismsDiseaseEnsureEpithelialEpithelial CellsEpitheliumExhibitsFemaleFundingFutureGene ExpressionGene ProteinsGenesHost DefenseImmune responseIn VitroInbreedingInfectionInfertilityInflammationInflammatoryInterferon Type IInterferon-alphaInterferon-betaInterferonsInvestigationKnockout MiceLiteratureMammalian OviductsMethodologyMouse StrainsMusOutcomePathogenesisPathologyPathology ReportPelvic Inflammatory DiseasePlayProductionPublishingReagentResearchResearch PersonnelRoleSexually Transmitted DiseasesSignal PathwaySuggestionTLR3 geneTestingUnited StatesUterusWild Type MouseWomanadaptive immune responseautocrinechemokinecytokinein vivomouse modelneutralizing antibodyoverexpressionparacrinepathogenprotein functionreceptorreproductive tractresponse
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.
衣原体感染引起的生殖道病理是对存在的免疫反应的结果
女性生殖道内的衣原体。先天免疫反应和获得性免疫反应都是作为宿主的一部分诱导的
对感染的防御,以及特定的细胞因子和趋化因子在调节这些防御机制中发挥作用。
因为我们之前发表的数据显示,TLR3缺乏会导致干扰素-β的合成显著减少
在OE细胞和小鼠感染鼠隐孢子虫的过程中,我们推测干扰素-β可能不是一个促成因素。
TLR3基因缺陷小鼠生殖道病理性的增加。我们进一步假设干扰素-β
相反,它是对CM感染的保护性免疫反应的必要组成部分。为了检验这些假设,我们
用105IFU cm经阴道感染野生型和干扰素-βKO小鼠,初步表明干扰素-βKO小鼠
与WT小鼠相比,Cm感染小鼠具有更高的衣原体载量和更多的生殖道病变。
我们的数据挑战了1型干扰素在衣原体感染的宿主反应中有害的范式
由其他研究人员利用干扰素α/β受体(IFNAR)KO小鼠建立。然而,令人兴奋的结果之一
我们对衣原体-TLR3相互作用机制的体外研究中,TLR3缺乏导致
几种干扰素α亚型的过度表达。这一意想不到的发现揭示了TLR3对干扰素α和
干扰素-β,从而在CM感染OE细胞的过程中刺激诱导干扰素-β,同时下调
干扰素α的表达。干扰素α在TLR3缺乏症中的过度表达提示干扰素α(而不是干扰素-β)可能是
导致TLR3缺陷小鼠生殖道病理增加的因素,并支持一种类型-
1干扰素加重衣原体引起的生殖道病理,其他人使用IFNAR KO小鼠报告。这项研究
针对特定目标的计划#1描述了使用CRISPR-Cas9产生近亲交配的敲除小鼠品系,该品系在
干扰素α亚型2、4、12和13的基因表达和蛋白功能。由于这四种亚型干扰素α代表
只有在Cm感染小鼠生殖道上皮过程中诱导的干扰素α亚型,这只四联KO小鼠将成为
Cm感染过程中干扰素α参与生殖道病理的重要试剂
在体外和体内都有。
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)
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WILBERT A DERBIGNY其他文献
WILBERT A DERBIGNY的其他文献
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{{ 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:
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