Impact of interferon λ signaling on lung macrophage function and type 17 immunity during bacterial super-infection following influenza
流感后细菌重复感染期间干扰素α信号对肺巨噬细胞功能和17型免疫的影响
基本信息
- 批准号:10602685
- 负责人:
- 金额:$ 4.77万
- 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:2023-05-01 至 2026-04-30
- 项目状态:未结题
- 来源:
- 关键词:Activities of Daily LivingAffectAlveolarAntigen PresentationAntigen-Presenting CellsAttenuatedBacterial AntigensBacterial InfectionsBenefits and RisksBiological AssayCD4 Positive T LymphocytesCause of DeathCellsComplicationDataDendritic CellsEnvironmentEnzyme-Linked Immunosorbent AssayEpithelial CellsEpitheliumExhibitsFamilyFlow CytometryFoundationsFutureHumanIFNGR1 geneIL17 geneImmuneImmune responseImmunityImpairmentIn VitroIncubatedInfectionInflammatoryInfluenzaInterferon Type IInterferon Type IIInterferon alphaInterferonsLabelLaboratoriesLungLung diseasesMacrophageMeasuresMethodsMorbidity - disease rateMucous MembraneMusMyelogenousMyeloid CellsOutcomeOvumPathway interactionsPhagocytosisPopulationPredispositionPrevalenceProcessProductionRecombinant InterferonResolutionRespiratory SystemRoleSecondary toSeveritiesSignal PathwaySignal TransductionStaphylococcus aureusStaphylococcus aureus infectionSyndromeTherapeuticViralVisualWild Type Mouseattenuationcell typecytokineexperimental studyextracellularfunctional outcomesin vitro Assayin vivoinfluenza infectioninsightinterleukin-22interstitiallung injurymethicillin resistant Staphylococcus aureusmonocytemortalityneutrophilpathogenreceptorreceptor expressionrecruitrespiratory pathogenresponsesuperinfectionuptake
项目摘要
Abstract
Lung diseases and syndromes caused by respiratory pathogens represent a leading cause of death worldwide.
Each year, influenza infections result in a significant number of fatalities, a majority of which are complicated by
secondary bacterial super-infection. Primary influenza infection has been shown to increase susceptibility to
secondary methicillin-resistant Staphylococcus aureus (MRSA) infection by altering the pulmonary host immune
response and damaging the lung epithelial barrier, leading to increased morbidity and mortality. Macrophages,
both lung-resident and those recruited to the lung, are important in super-infection resolution as they engulf,
degrade, and present bacterial antigen to adaptive immune cells, ultimately leading to activation of type 17 cells,
which promote pathogen clearance. While the role of interferon-(IFN)α/β during super-infection has been well
characterized, type III IFNs have not been as extensively studied within the context of the lung. Data shows that
IFNα/β are involved in type 17 attenuation after primary influenza infection, which may indicate that IFNλ exhibits
similar inhibitory functions due to overlapping signaling pathways, although the potential for unique functions on
lung cells is unresolved.
Our lab has preliminary data suggesting that administration of exogenous IFNλ during super-infection reduces
bacterial uptake by neutrophils and monocyte-derived cells, but the specific cell subsets impacted are unknown.
I hypothesize that lung-resident macrophages are sensitive to IFNλ and that IFNλ signaling impairs
phagocytosis and the type 17 immune response during super-infection. In the proposed studies, I will
determine which myeloid subsets express the IFNλ receptor (IFNLR1) and identify how intact or disrupted IFNλ
signaling broadly impacts lung injury and resolution after infection. More specifically, these experiments will
determine how IFNλ impacts MRSA uptake and the initiation of a type 17 immune response during super-
infection. IFNλ administration has been considered for therapeutic potential, and the outcomes of this proposal
will shed light on potential caveats to the use of IFNλ as a possible treatment method during super-infection.
Further, demonstration of the effects of IFNλ on myeloid cells will potentially be applicable to several other
settings where an antiviral interferon response is observed.
摘要
由呼吸道病原体引起的肺部疾病和综合征是全世界主要的死亡原因。
每年,流感感染都会导致相当数量的死亡,其中大多数是由
继发性细菌重叠感染。原发流感感染已被证明增加了对
耐甲氧西林金黄色葡萄球菌继发感染与肺部宿主免疫功能的关系
反应和破坏肺上皮屏障,导致发病率和死亡率增加。巨噬细胞,
无论是常驻肺部的还是被招募到肺部的,在吞噬超级感染的过程中都是重要的,
降解细菌抗原并将其呈递给适应性免疫细胞,最终导致17型细胞的激活,
促进病原体清除的物质。而干扰素α/β在双重感染中的作用一直很好
因此,III型干扰素尚未在肺脏中得到广泛的研究。数据显示,
干扰素α/β参与了流感病毒感染后17型病毒的减毒作用,提示干扰素λ表现出
相似的抑制功能,由于重叠的信号通路,尽管潜在的独特功能
肺细胞尚未分解。
我们的实验室有初步数据表明,在双重感染期间给予外源性干扰素λ可以减少
中性粒细胞和单核细胞来源的细胞对细菌的摄取,但受影响的特定细胞亚群尚不清楚。
我假设肺巨噬细胞对干扰素λ敏感,并且干扰素λ信号受损。
双重感染时的吞噬作用和17型免疫反应。在建议的研究中,我会
确定哪些髓系亚群表达干扰素λ受体,并确定干扰素λ是如何完整或被破坏的
信号广泛影响肺损伤和感染后的解决。更具体地说,这些实验将
确定干扰素λ如何影响耐甲氧西林金黄色葡萄球菌摄取和启动17型免疫反应
感染。干扰素λ的使用已经被认为具有治疗潜力,这项提议的结果是
将阐明在双重感染期间使用干扰素λ作为一种可能的治疗方法的潜在警告。
此外,干扰素λ对髓系细胞的影响的演示可能也适用于其他几种细胞。
观察到抗病毒干扰素应答的环境。
项目成果
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