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

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死亡的主要原因。 每年,流感感染导致大量死亡,其中大多数是并发症, 继发性细菌重叠感染。原发性流感感染已被证明会增加对以下疾病的易感性 通过改变肺部宿主免疫而继发耐甲氧西林金黄色葡萄球菌(MRSA)感染 这可能会导致肺组织的炎症反应,并破坏肺上皮屏障,导致发病率和死亡率增加。巨噬细胞, 无论是肺部居民和那些招募到肺部,是重要的超级感染决议,因为他们吞噬, 降解,并将细菌抗原呈递给适应性免疫细胞,最终导致17型细胞的活化, 从而促进病原体清除。而干扰素α/β在重复感染中的作用已被充分研究 尽管III型IFN是典型的,但在肺的背景下尚未进行广泛的研究。数据显示 IFNα/β参与原发性流感感染后17型减毒,这可能表明IFNλ表现出 由于重叠的信号传导途径,类似的抑制功能,尽管在 肺细胞未解决。 我们的实验室有初步的数据表明,在双重感染期间给予外源性IFNλ可以减少 中性粒细胞和单核细胞衍生细胞的细菌摄取,但受影响的特定细胞亚群尚不清楚。 我假设肺内巨噬细胞对IFNλ敏感,IFNλ信号传导受损, 吞噬作用和17型免疫反应。在拟议的研究中,我将 确定哪些髓系亚群表达IFNλ受体(IFNLR 1),并确定完整或破坏的IFNλ 信号传导广泛影响感染后的肺损伤和消退。更具体地说,这些实验将 确定IFNλ如何影响MRSA摄取和超级期间17型免疫应答的启动, 感染IFNλ给药已被认为具有治疗潜力, 将阐明使用IFNλ作为双重感染期间可能的治疗方法的潜在警告。 此外,IFNλ对骨髓细胞的作用的证明将潜在地适用于几种其他的骨髓细胞。 观察到抗病毒干扰素反应的环境。

项目成果

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