Using Legionella-amoeba co-evolution to reveal new modes of immunity and pathogenesis
利用军团菌-阿米巴共同进化揭示新的免疫模式和发病机制
基本信息
- 批准号:10392755
- 负责人:
- 金额:$ 1.41万
- 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:2020-07-01 至 2022-06-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAmoeba genusAnimalsAnti-Bacterial AgentsAntibioticsAttentionBacteriaBacterial GenesBacterial InfectionsBacteriologyBiological ModelsBiologyCandidate Disease GeneCellsCellular biologyConflict (Psychology)CytosolDetectionDictyosteliumDiseaseDisease OutbreaksEnvironmentEukaryotic CellEvolutionGenesGeneticGenetic ScreeningGenetic TranscriptionGenomeGenomicsHealthHumanImmuneImmune responseImmune systemImmunityInfectionIronLeadLegionellaLegionella pneumophilaMammalian CellMicrobeModelingMolecularMolecular EvolutionNatural ImmunityOrganismOutcomePathogenesisPathway interactionsPlayPneumoniaPredispositionProteinsRaceResearchResourcesRoleStructureSystemTestingToll-like receptorsTrainingTransgenic OrganismsViral Pathogenesisarmbacterial fitnessbacterial geneticsbasecomparative genomicsexperienceexperimental studyfightingfitnessgenetic approachgenetic evolutiongenome-widegenome-wide analysishost-microbe interactionsimprintinnovationinterdisciplinary approachmanmembermicrobialmolecular shapemutantnovelnovel strategiesopportunistic pathogenpathogenpathogen genomepathogenic bacteriapressurepreventprogramsresidencetransposon sequencing
项目摘要
PROJECT SUMMARY
Legionella pneumophila is an opportunistic bacterial pathogen that causes outbreaks of a lethal, pneumonia-
like disease. Although human infections are evolutionary “dead ends” for these bacteria, Legionella
nevertheless carry extensive molecular arsenals to attack human cells due to their adaptation to their natural
hosts, environmental amoebae. Residence in amoebae also protects Legionella from antibiotics and other
efforts to eliminate the bacteria from man-made structures, perpetuating human outbreaks. Revealing how
Legionella exploits host amoebae—particularly steps vulnerable to disruption—therefore has direct benefits for
human health. This proposal will investigate how molecular “arms races” between Legionella and amoebae
have shaped the molecular toolkit of this pathogen, and address the specific hypothesis that Legionella
secreted effector proteins are engaged in arms races with amoeba immune pathways. The experimental
tractability and evolutionary resources available for Legionella and amoebae make this a powerful host-
microbe model system, where it is possible to test the functional consequences of evolutionary innovation in
both host and microbe. Aim 1 will investigate how Legionella has been impacted by such an arms race.
Evolutionary approaches will analyze this organism's enormous arsenal of molecular weaponry, the type IV
effectors, to identify genes and residues likely engaged in arms races with hosts. Bacterial genetics will then be
used to functionally test evolutionary hypotheses about which genes or residues are critical for pathogen
fitness. These studies will begin with the mavN gene, which appears to be engaged in an evolutionary “battle
for iron” within host cells. In addition to such competitions for resources, many pathogens have evolved
strategies to evade detection by host immune systems. High-throughput transposon-sequencing approaches
will be used to identify bacterial genes that are required for fitness within Dictyostelium amoebae, particularly
those that interact with amoeba immunity. These experiments will reveal which Legionella proteins have
experienced strong selective pressures in amoeba hosts. Aim 2 will examine the host genes likely to place
strong selective pressures on Legionella through studies of amoeba immune defenses. The Dictyostelium TirA
protein is related to Toll-like receptors in animals, and helps the amoebae to resist Legionella infection.
However, beyond these basic facts, almost nothing is known about amoeba immunity. This aim will further
characterize the activity of the TirA immune pathway, identifying additional members of the immune pathway
and transcriptional targets. Evolutionary and unbiased genetic approaches will highlight additional arms of the
amoeba immune response that respond to Legionella infection. The proposal will combine the applicant's
background in evolution, genetics, and host-microbe interactions with the Malik lab's expertise in evolutionary
arms races. This interdisciplinary approach will also provide her new training in bacteriology and amoebal
biology, to uncover how evolutionary arms races in the natural environment have armed Legionella for human
infections.
项目总结
嗜肺军团菌是一种机会性的细菌病原体,会导致致命肺炎的爆发-
就像疾病一样。尽管人类感染是这些细菌在进化上的“死胡同”,但军团菌
尽管如此,携带大量的分子武器库来攻击人类细胞,因为它们适应了自然的
主持人,环境阿米巴虫。在阿米巴的栖息地也可以保护军团菌免受抗生素和其他
努力消除人造建筑物中的细菌,使人类疫情永久化。揭示如何
军团菌利用宿主阿米巴--特别是容易受到破坏的步骤--因此对
人类健康。这项提案将调查军团菌和阿米巴之间的分子“军备竞赛”
已经形成了这种病原体的分子工具箱,并解决了军团菌
分泌的效应蛋白通过阿米巴免疫途径参与军备竞赛。实验性的
军团菌和阿米巴可利用的可驯性和进化资源使其成为强大的宿主-
微生物模型系统,在那里可以测试进化创新的功能后果
无论是宿主还是微生物。AIM 1将调查军团菌是如何受到这种军备竞赛的影响的。
进化论方法将分析这种有机体巨大的分子武器库--IV型
效应器,以识别可能与宿主进行军备竞赛的基因和残基。到那时,细菌遗传学将
用于从功能上测试关于哪些基因或残基对病原体至关重要的进化假说
健身。这些研究将从mavn基因开始,它似乎正在进行一场进化的“战斗”
在宿主细胞内寻找“铁”。除了这种对资源的竞争,许多病原体已经进化
逃避宿主免疫系统检测的策略。高通量转座子测序方法
将被用来鉴定适合Dictyostelialamobae的细菌基因,特别是
那些与阿米巴免疫力相互作用的细胞。这些实验将揭示军团菌的哪些蛋白
在阿米巴宿主中经历了强烈的选择压力。目标2将检查宿主基因可能放置在
通过对阿米巴免疫防御的研究,军团菌面临着强大的选择压力。蒂拉网柄网柄菌
在动物中,蛋白质与Toll样受体有关,并帮助阿米巴抵抗军团菌感染。
然而,除了这些基本事实外,人们对阿米巴免疫几乎一无所知。这一目标将进一步
表征Tira免疫途径的活性,确定免疫途径的其他成员
和转录靶标。进化和无偏见的遗传方法将突出
对军团菌感染作出反应的阿米巴免疫反应。该提案将结合申请人的
具有Malik实验室在进化方面的专业知识的进化、遗传学和宿主-微生物相互作用背景
军备竞赛。这种跨学科的方法还将为她提供细菌学和阿米巴变形虫方面的新培训
生物学,揭示自然环境中进化的军备竞赛如何武装人类军团菌
感染。
项目成果
期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
L. pneumophila resists its self-harming metabolite HGA via secreted factors and collective peroxide scavenging.
- DOI:10.1128/mbio.01207-23
- 发表时间:2023-10-31
- 期刊:
- 影响因子:6.4
- 作者:
- 通讯作者:
Eukaryotic CD-NTase, STING, and viperin proteins evolved via domain shuffling, horizontal transfer, and ancient inheritance from prokaryotes.
- DOI:10.1371/journal.pbio.3002436
- 发表时间:2023-12
- 期刊:
- 影响因子:9.8
- 作者:Culbertson, Edward M.;Levin, Tera C.
- 通讯作者:Levin, Tera C.
mSphere of Influence: How I Learned to Love Bacteria and their Tangled Evolutionary Tree.
- DOI:10.1128/msphere.00780-21
- 发表时间:2021-10-27
- 期刊:
- 影响因子:4.8
- 作者:Levin TC
- 通讯作者:Levin TC
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Tera Catherine Levin其他文献
Tera Catherine Levin的其他文献
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{{ truncateString('Tera Catherine Levin', 18)}}的其他基金
The origins and evolution of eukaryotic antibacterial defenses
真核生物抗菌防御的起源和进化
- 批准号:
10711117 - 财政年份:2023
- 资助金额:
$ 1.41万 - 项目类别:
Using Legionella-amoeba co-evolution to reveal new modes of immunity and pathogenesis
利用军团菌-阿米巴共同进化揭示新的免疫模式和发病机制
- 批准号:
10166988 - 财政年份:2020
- 资助金额:
$ 1.41万 - 项目类别:
Using Legionella-amoeba co-evolution to reveal new modes of immunity and pathogenesis
利用军团菌-阿米巴共同进化揭示新的免疫模式和发病机制
- 批准号:
10200673 - 财政年份:2020
- 资助金额:
$ 1.41万 - 项目类别: