Innate immunity and inflammatory response of macrophages to Legionella infection
巨噬细胞对军团菌感染的先天免疫和炎症反应
基本信息
- 批准号:10466923
- 负责人:
- 金额:$ 38.25万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-09-14 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalAdaptor Signaling ProteinAmylasesAnimal ModelAnti-Inflammatory AgentsAttenuatedBacterial InfectionsBindingBypassCase StudyCrystallizationCytosolDataExhibitsGlucoseGlycogenGlycolysisGrowthHumanImmuneIn VitroInfectionInfection ControlInflammatoryInflammatory ResponseInnate Immune ResponseKnowledgeLegionellaLegionella pneumophilaLegionnaires&apos DiseaseLungLysosomesMacrophage ActivationMediatingMembraneMetabolismMorbidity - disease rateMusNatural ImmunityPathway interactionsPhenotypePhosphotyrosineProteinsRoleSideSignal TransductionStructureSurfaceTestingUp-RegulationVacuoleaerobic glycolysisarmcommunity acquired pneumoniacytokinediabetic patientin vivoinnate immune mechanismsinnate immune pathwaysmacrophagemonocytemortalitymutantnovelpathogenpathogenic bacteriaresponse
项目摘要
Project Summary
Depending on the signals in vitro, macrophages can undergo transient and reversible differentiation
into two main subsets: pro-inflammatory “M1” (classically activated) or anti-inflammatory “M2”
(alternatively activated) phenotype. Upon exposure of macrophages to high levels of glucose in vitro
or in diabetic patients in vivo, they undergo differentiation and activation into a M1 pro-inflammatory
state, which produces pro-inflammatory cytokines mediated by cellular reprogramming of metabolism
through upregulating aerobic glycolysis. The M1 pro-inflammatory differentiation of macrophages is
an import arm of the innate immune response to control bacterial infections. Our preliminary data
show that when macrophages engulf the intracellular bacterial pathogen Legionella pneumophila
(Lp), they rapidly respond by differentiation into an activated M1-like pro-inflammatory phenotype.
Despite this rapid macrophage pro-inflammatory activation, the Legionella-containing vacuole
(LCV) bypasses macrophage activation by limiting its fusion to lysosomes. We show that the early
M1-like pro-inflammatory differentiation of human monocytes-derived macrophages (hMDMs) to
Lp is an innate immune response to cytosolic hyper-glucose generated through rapid degradation of
glycogen by the injected Legionella amylase (LamA) effector. We discovered that Lp has evolved a
lysosomal degradation bypass pathway within the pro-inflammatory hMDMs by injecting the MavE
effector, which becomes localized in a micro-domain on the cytosolic side of the LCV membrane.
The mavE-deficient mutant is targeted by hMDMs to the lysosomes for degradation, and the mutant
is totally attenuated in vitro and in vivo. We have resolved the novel three dimensional crystal structure
of MavE, which shows a cytosolic surface-exposed domain with an NPxY eukaryotic motif involved
in binding to phosphotyrosine-binding adaptor proteins. Our central hypothesis is: the M1-like pro-
inflammatory activation of hMDMs to Lp infection is an innate immune response to the cytosolic
hyper-glucose elicited by LamA, and the pathogen utilizes MavE to bypass the innate immune
macrophage pathway of lysosomal degradation. To test the hypothesis, our specific aims are:
Specific Aim I: The mechanisms of M1-like pro-inflammatory differentiation of hMDMs in
response to the effect of LamA; and Specific Aim II: The mechanisms of evasion of the innate
macrophage function of lysosomal degradation through utilization of a lysosomes bypass
pathway mediated by MavE. Upon completion of our proposed studies, we will discover the
mechanism of the innate pro-inflammatory response of macrophages to Lp and the lysosomal
degradation bypass pathway maneuvered by the pathogen to avoid a fatal fate.
项目总结
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)
Evolution and Adaptation of Legionella pneumophila to Manipulate the Ubiquitination Machinery of Its Amoebae and Mammalian Hosts.
- DOI:10.3390/biom11010112
- 发表时间:2021-01-15
- 期刊:
- 影响因子:5.5
- 作者:Price CTD;Abu Kwaik Y
- 通讯作者:Abu Kwaik Y
Evasion of phagotrophic predation by protist hosts and innate immunity of metazoan hosts by Legionella pneumophila.
- DOI:10.1111/cmi.12971
- 发表时间:2019-01
- 期刊:
- 影响因子:3.4
- 作者:Best AM;Abu Kwaik Y
- 通讯作者:Abu Kwaik Y
An Indispensable Role for the MavE Effector of Legionella pneumophila in Lysosomal Evasion.
- DOI:10.1128/mbio.03458-20
- 发表时间:2021-02-09
- 期刊:
- 影响因子:6.4
- 作者:Vaughn B;Voth K;Price CT;Jones S;Ozanic M;Santic M;Cygler M;Abu Kwaik Y
- 通讯作者:Abu Kwaik Y
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Yousef A Abu Kwaik其他文献
Yousef A Abu Kwaik的其他文献
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{{ truncateString('Yousef A Abu Kwaik', 18)}}的其他基金
Legionella-Polymorphonuclear Leukocytes Interaction
军团菌-多形核白细胞相互作用
- 批准号:
10057609 - 财政年份:2020
- 资助金额:
$ 38.25万 - 项目类别:
Legionella-Polymorphonuclear Leukocytes Interaction
军团菌-多形核白细胞相互作用
- 批准号:
10197041 - 财政年份:2020
- 资助金额:
$ 38.25万 - 项目类别:
Innate immunity and inflammatory response of macrophages to Legionella infection
巨噬细胞对军团菌感染的先天免疫和炎症反应
- 批准号:
10238822 - 财政年份:2018
- 资助金额:
$ 38.25万 - 项目类别:
Molecular and Cellular Pathogenesis of Legionella
军团菌的分子和细胞发病机制
- 批准号:
9052132 - 财政年份:2015
- 资助金额:
$ 38.25万 - 项目类别:
Molecular and Cellular Pathogenesis of Legionella
军团菌的分子和细胞发病机制
- 批准号:
8975821 - 财政年份:2015
- 资助金额:
$ 38.25万 - 项目类别:
Modulation of apoptosis by Legionella Pneumophila
嗜肺军团菌对细胞凋亡的调节
- 批准号:
8089565 - 财政年份:2007
- 资助金额:
$ 38.25万 - 项目类别:
Modulation of apoptosis by Legionella Pneumophila
嗜肺军团菌对细胞凋亡的调节
- 批准号:
7883357 - 财政年份:2007
- 资助金额:
$ 38.25万 - 项目类别:
Modulation of apoptosis by Legionella Pneumophila
嗜肺军团菌对细胞凋亡的调节
- 批准号:
7467343 - 财政年份:2007
- 资助金额:
$ 38.25万 - 项目类别:














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