Interleukin-27 in host response to Legionella infection
Interleukin-27 在宿主对军团菌感染的反应中
基本信息
- 批准号:10745091
- 负责人:
- 金额:$ 70.37万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-07-01 至 2027-06-30
- 项目状态:未结题
- 来源:
- 关键词:AblationAccidentsAcuteAcute Respiratory Distress SyndromeAdoptive Cell TransfersAerosolsAlveolar MacrophagesAmoeba genusAntibodiesBacteriaBindingBody Weight decreasedBronchoalveolar LavageBronchoalveolar Lavage FluidCell CommunicationCell MaturationCellsCellular Indexing of Transcriptomes and Epitopes by SequencingCessation of lifeChimera organismChimeric ProteinsChronicClinicalCytoprotectionDataDefectDendritic CellsDimensionsDiseaseEngineeringEnvironmentFamilyFutureGene DeletionGenetic TranscriptionHabitatsHistologyHumanIL27RA geneITGAM geneImmuneImmune responseImmunologic ReceptorsImmunosuppressionImpairmentIncidenceInfectionInfiltrationInflammationInflammatory ResponseInhalationInterferon Type IIInterleukin-12Interleukin-6InterleukinsInvadedKnock-outKnowledgeLegionellaLegionella longbeachaeLegionella pneumophilaLegionellaceaeLegionellosisLegionnaires&apos DiseaseLigationLungLung infectionsLymphocyteMacrophageMediatingMediatorMolecularMononuclearMusMyeloid CellsNK Cell ActivationNatural Killer CellsNeutrophil InfiltrationOutcomePD-1/PD-L1ParasitesPathogenesisPathway interactionsPatientsPattern recognition receptorPhagocytesPhagocytosisPhosphoproteinsPhosphorylationPlayPneumoniaProductionReceptor ActivationRegulatory T-LymphocyteReporterReportingResearchResistanceRespiratory physiologyRoleSTAT1 geneSTAT3 geneSamplingSeveritiesSignal PathwaySignal TransductionSolidSourceSurrogate EndpointT cell responseT-Cell ActivationT-LymphocyteTestingUnited StatesVacuoleVirulentWild Type Mouseatypical pneumoniacell typecytokineexperimental studyhigh riskimmunopathologyimprovedinnate immune sensinginsightmonocytemortalitymultidimensional datanovelorgan injurypathogenprogramsprotein biomarkersreceptortargeted treatmenttranscriptomeγδ T cells
项目摘要
Project Summary: Legionellosis (Legionnaires’ disease) is a form of atypical pneumonia with a steep rising
incidence in the United States. The mortality rates of patients stagnate around 3-30% despite treatment.
Legionellosis is caused by facultative, intracellular bacteria of the Legionellaceae family, which reside in natural
and engineered aquatic habitats. Inhalation of contaminated aerosols can lead to infection, evasion of pathogen
eradication and continuous replication in Legionella containing vacuoles inside alveolar macrophages (AMs).
The ensuing inflammation promotes an infiltration of myeloid cells and lymphocytes into lungs. These immune
cells communicate with each other via cytokines. Interleukin-27 (IL-27) is a heterodimeric cytokine formed by
non-covalent interactions of the subunits p28 and EBI3. IL-27 is induced by pattern recognition receptor (PRR)
activation in mononuclear phagocytes (AMs, monocytes, dendritic cells). IL-27 ligation with its unique receptor
chain, IL-27RA, on lymphocytes initiates STAT1/STAT3 phosphorylation. IL-27RA signaling initiates pleiotropic
programs, which can first intensify acute inflammation and later limit prolonged T cell activation. Our preliminary
data support the new concept that IL-27 is a critical player of the host response to Legionella infection. IL-27 is
elevated in broncho-alveolar lavage fluids of human patients with Legionnaires’ disease and IL-27RA deficient
mice are more resistant to infection. Here, we propose to test the central hypothesis that IL-27 is produced by
Legionella infected mononuclear phagocytes and initiates dichotomous programs in lymphocytes, that include
the protective activation of NK cells and adverse T cell-mediated immunosuppression in lungs. Aim 1) To pinpoint
the cellular source(s) of IL-27 during Legionellosis within the subsets of lung mononuclear phagocytes. We aim
to assess the contribution of relevant PRR immunosensors for IL-27 induction by L. pneumophila. Samples from
Legionnaires’ disease patients will be studied for associations of IL-27 with the PD-1/PD-L1 axis and soluble
markers of immunopathology. Aim 2) To characterize the functional consequences of constitutive IL-27RA
ablation in infected IL-27RA-/- mice, and to study the host response programs by single-cell, multi-dimensional
proteotranscriptomics (CITE-Seq/Total-Seq). We will also evaluate neutralizing IL-27 antibodies and an
engineered decoy receptor to improve pneumonia severity in mice. Aim 3) Based on preliminary data, we aim to
study the altered inflammatory response of our novel conditional mice with NK cell-specific deletion of IL-27RA.
We will investigate whether NK cell maturation is associated with a switch of IL-27RA controlled transcriptional
programs through engaging non-STAT phosphoprotein signaling. Aim 4) To investigate the roles of IL-27RA in
conventional and unconventional T cells with a mechanistic focus on co-inhibitory/co-stimulatory receptors during
lung infection with L. pneumophila and L. longbeachae in mice. In summary, the proposed studies will test the
novel concept that IL-27 plays a critical role for the lung host response and outcome of Legionellosis and that IL-
27RA initiates selective programs in NK cells versus T cells.
项目摘要:军团病是一种急剧上升的非典型肺炎
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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Markus Bosmann其他文献
Markus Bosmann的其他文献
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{{ truncateString('Markus Bosmann', 18)}}的其他基金
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MAVS 在细菌性脓毒症中的作用逆转
- 批准号:
10439602 - 财政年份:2018
- 资助金额:
$ 70.37万 - 项目类别:
Role reversal of MAVS in bacterial sepsis
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