Metabolic adaptions of Mycobacterium tuberculosis at diverse host-pathogen interfaces
Metabolic adaptions of Mycobacterium tuberculosis at diverse host-pathogen interfaces
批准号:
10630740
负责人:
DAVID Branch MOODY
金额:
$54.38万
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
未结题
起止时间:
2021-07-01 至 2026-04-30
关键词:
Animal ModelAntitubercular AgentsBacterial GenesCRISPR interferenceCRISPR libraryDiseaseDisease OutcomeDrug TargetingEncapsulatedEpithelialEssential GenesFundingGenesGeneticGenetic VariationGenome MappingsGenotypeGrantGranulomaGrowthHouse miceHumanInbred MouseInbred StrainInbred Strains MiceIndividualInfectionIntegration Host FactorsLesionLibrariesLinkLipidsMeasuresMetabolicMetabolismModelingMosaicismMouse StrainsMusMycobacterium tuberculosisNucleotidesOutcomeParentsPhenotypePopulationPre-Clinical ModelProcessQuantitative Trait LociRecombinantsReproducibilityResolutionResourcesShapesSiteSystemTechnologyTuberculosisVariantVirulenceWorkbacterial geneticsbasecohortdisease diagnosticgenome wide association studygenome-widegenomic locushuman diseaseimprovedin vivomammalian genomemouse modelmutantnovelparent grantpathogenreference genomeresponsestemtraittransposon sequencingtuberculosis treatment
中文摘要
结核分枝杆菌在不同宿主-病原体界面的代谢适应
摘要
确定结核分枝杆菌(Mtb)代谢产物影响人类的机制
结核病的诊断和治疗将需要实施模型动物系统
它们既易于处理,又忠实地复制了在人类中观察到的结核病状态。克服
有限的遗传和表型多样性显示在标准C57 BL/6J,在这里,我们建议利用
协作杂交(CC)小鼠的综合小组,一组遗传多样的重组近交系小鼠,
小鼠我们以前已经表明,CC包括广泛的结核病特征,
感染微环境,超过了在经典近交系中观察到的表型谱。基于
在先前的TnSeq研究中以及作为母TBRU资助的一部分("Metabolic determinants of Mtb virtuality,
脆弱性和变异"; 1U19AI162584 - 02),我们对与结核分枝杆菌相关的结核分枝杆菌代谢基因进行了排序,
感染人类的Mtb菌株中的毒力或控制脂质变异。19个高价值结核分枝杆菌代谢基因
在常规C57 BL/6J(BL6)小鼠品系中,仅一种控制生长。但超过
当在CC小鼠品系中筛选时,所研究的一半突变体显示出体内生长表型。此外,本发明还
通过研究几种CC宿主的遗传背景,其中单个细菌基因做或不做
通过控制体内Mtb存活,我们能够开始定义控制Mtb应答的宿主因素。的
目前的申请现在将扩展这些研究,以专注于CRISPRi的靶向细菌脂质文库
突变体与CC小鼠的综合小组一起。通过感染60种不同的CC基因型,
靶向脂质CRISPRi文库,Mtb的代谢脆弱性将在
基因多样的宿主通过使用细菌突变体丰度作为表型性状,我们将进行
在CC面板上进行数量性状基因座(QTL)作图,以鉴定脂质代谢相关的宿主基因座。
Mtb感染的要求。总之,这些双重宿主和病原体的方法将确定宿主-Mtb
脂质相互作用,可以针对结核病治疗。
英文摘要
Metabolic adaptions of Mycobacterium tuberculosis at diverse host-pathogen interfaces
ABSTRACT
Defining the mechanisms through which Mycobacterium tuberculosis (Mtb) metabolites impact human
tuberculosis (TB) disease, diagnostics and treatment will require the implementation of model animal systems
that are both tractable and faithfully replicate the TB disease states observed in humans. To overcome the
limited genetic and phenotypic diversity shown in standard C57BL/6J, here we propose to leverage the
comprehensive panel of Collaborative Cross (CC) mice, a genetically diverse panel of recombinant inbred
mice. We have previously shown that the CC encompasses a broad spectrum of TB disease traits and
infection microenvironments, exceeding the phenotypic spectrum observed in classical inbred strains. Based
on previous TnSeq studies and as part of the parent TBRU grant (“Metabolic determinants of Mtb virulence,
vulnerability and variation”; 1U19AI162584-02), we have ranked Mtb metabolic genes that were linked to Mtb
virulence or control lipid variation in Mtb strains that infect humans. Of 19 high value Mtb metabolic genes
identified, only one controlled growth in the conventional C57BL/6J (BL6) mouse strain. However, more than
half the mutants studied showed in vivo growth phenotypes when screened across CC mouse strains. Further,
through study of several of the CC host genetic backgrounds in which individual bacterial genes do or do not
control in vivo Mtb survival, we are able to start to define the host factors in control of Mtb response. The
current application will now extend these studies to focus on a targeted bacterial lipid library of CRISPRi
mutants in conjunction with the comprehensive panel of CC mice. By infecting 60 distinct CC genotypes with
the targeted lipid CRISPRi library, the metabolic vulnerabilities of Mtb will be comprehensively defined in
genetically diverse hosts. By using bacterial mutant abundance as a phenotypic trait, we will conduct
quantitative trait loci (QTL) mapping across the CC panel to identify the host loci underlying the lipid
requirements of Mtb infection. Altogether these dual host and pathogen approaches will identify the host-Mtb
lipid interactions that can be targeted for tuberculosis treatment.
期刊论文(8)
专著(0)
科研奖励(0)
会议论文
DOI:
10.1002/jia2.26081
发表时间:
2023-03
期刊:
Journal of the International AIDS Society
影响因子:
6
作者:
[]
通讯作者:
DOI:
10.3389/fcimb.2022.997283
发表时间:
2022
期刊:
Frontiers in cellular and infection microbiology
影响因子:
5.7
作者:
[]
通讯作者:
DOI:
10.1164/rccm.202110-2378oc
发表时间:
2022-07-15
期刊:
American journal of respiratory and critical care medicine
影响因子:
24.7
作者:
[]
通讯作者:
Chemical Biological Discovery of Lipid Virulence Factors in the Major Bacterial Pathogens
-
批准号:10518252
-
项目类别:
-
资助金额:$64.25万
-
财政年份:2022
-
负责人:DAVID Branch MOODY
-
依托单位:
Chemical Biological Discovery of Lipid Virulence Factors in the Major Bacterial Pathogens
-
批准号:10651853
-
项目类别:
-
资助金额:$62.28万
-
财政年份:2022
-
负责人:DAVID Branch MOODY
-
依托单位:
Profiling and Mapping Core
-
批准号:10612026
-
项目类别:
-
资助金额:$46.07万
-
财政年份:2021
-
负责人:DAVID Branch MOODY
-
依托单位:
Study of M. tuberculosis under human host selection to identify virulence and barrier lipids (Project 1)
-
批准号:10612035
-
项目类别:
-
资助金额:$25.84万
-
财政年份:2021
-
负责人:DAVID Branch MOODY
-
依托单位:
Administrative Core
-
批准号:10271479
-
项目类别:
-
资助金额:$14.72万
-
财政年份:2021
-
负责人:DAVID Branch MOODY
-
依托单位:
Administrative Core
-
批准号:10612024
-
项目类别:
-
资助金额:$16.25万
-
财政年份:2021
-
负责人:DAVID Branch MOODY
-
依托单位:
Profiling and Mapping Core
-
批准号:10271480
-
项目类别:
-
资助金额:$45.07万
-
财政年份:2021
-
负责人:DAVID Branch MOODY
-
依托单位:
Profiling and Mapping Core
-
批准号:10438913
-
项目类别:
-
资助金额:$45.95万
-
财政年份:2021
-
负责人:DAVID Branch MOODY
-
依托单位:
Metabolic determinants of Mtb virulence, vulnerability and variation
-
批准号:10438911
-
项目类别:
-
资助金额:$257.81万
-
财政年份:2021
-
负责人:DAVID Branch MOODY
-
依托单位:
Metabolic determinants of Mtb virulence, vulnerability and variation
-
批准号:10612023
-
项目类别:
-
资助金额:$256.65万
-
财政年份:2021
-
负责人:DAVID Branch MOODY
-
依托单位:
Metabolic determinants of Mtb virulence, vulnerability and variation
-
批准号:10271478
-
项目类别:
-
资助金额:$254.73万
-
财政年份:2021
-
负责人:DAVID Branch MOODY
-
依托单位:
Administrative Core
-
批准号:10438912
-
项目类别:
-
资助金额:$15.68万
-
财政年份:2021
-
负责人:DAVID Branch MOODY
-
依托单位:
Study of M. tuberculosis under human host selection to identify virulence and barrier lipids (Project 1)
-
批准号:10438917
-
项目类别:
-
资助金额:$22.9万
-
财政年份:2021
-
负责人:DAVID Branch MOODY
-
依托单位:
Study of M. tuberculosis under human host selection to identify virulence and barrier lipids (Project 1)
-
批准号:10271484
-
项目类别:
-
资助金额:$26.04万
-
财政年份:2021
-
负责人:DAVID Branch MOODY
-
依托单位:
Metabolic factors that control the spectrum of human tuberculosis
-
批准号:9211996
-
项目类别:
-
资助金额:$304.45万
-
财政年份:2015
-
负责人:DAVID Branch MOODY
-
依托单位:
Metabolic factors that control the spectrum of human tuberculosis
-
批准号:10089381
-
项目类别:
-
资助金额:$250.41万
-
财政年份:2015
-
负责人:DAVID Branch MOODY
-
依托单位:
Role of Tuberculosinyl Metabolites in M. Tuberculosis Virulence
-
批准号:9207094
-
项目类别:
-
资助金额:$44.38万
-
财政年份:2015
-
负责人:DAVID Branch MOODY
-
依托单位:
Metabolic factors that control the spectrum of human tuberculosis
-
批准号:8693227
-
项目类别:
-
资助金额:$273.85万
-
财政年份:2015
-
负责人:DAVID Branch MOODY
-
依托单位:
Administrative Core
-
批准号:10089391
-
项目类别:
-
资助金额:$33.46万
-
财政年份:2015
-
负责人:DAVID Branch MOODY
-
依托单位:
Role of Tuberculosinyl Metabolites in M. Tuberculosis Virulence
-
批准号:8996551
-
项目类别:
-
资助金额:$54.43万
-
财政年份:2015
-
负责人:DAVID Branch MOODY
-
依托单位:
海外基金