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

• 批准号: 10602685
• 负责人: Danielle Antos
• 金额: $ 4.77万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10602685
• 关键词: Activities of Daily Living; Affect; Alveolar; Antigen Presentation; Antigen-Presenting Cells; Attenuated; Bacterial Antigens; Bacterial Infections; Benefits and Risks; Biological Assay; CD4 Positive T Lymphocytes; Cause of Death; Cells; Complication; Data; Dendritic Cells; Environment; Enzyme-Linked Immunosorbent Assay; Epithelial Cells; Epithelium; Exhibits; Family; Flow Cytometry; Foundations; Future; Human; IFNGR1 gene; IL17 gene; Immune; Immune response; Immunity; Impairment; In Vitro; Incubated; Infection; Inflammatory; Influenza; Interferon Type I; Interferon Type II; Interferon alpha; Interferons; Label; Laboratories; Lung; Lung diseases; Macrophage; Measures; Methods; Morbidity - disease rate; Mucous Membrane; Mus; Myelogenous; Myeloid Cells; Outcome; Ovum; Pathway interactions; Phagocytosis; Population; Predisposition; Prevalence; Process; Production; Recombinant Interferon; Resolution; Respiratory System; Role; Secondary to; Severities; Signal Pathway; Signal Transduction; Staphylococcus aureus; Staphylococcus aureus infection; Syndrome; Therapeutic; Viral; Visual; Wild Type Mouse; attenuation; cell type; cytokine; experimental study; extracellular; functional outcomes; in vitro Assay; in vivo; influenza infection; insight; interleukin-22; interstitial; lung injury; methicillin resistant Staphylococcus aureus; monocyte; mortality; neutrophil; pathogen; receptor; receptor expression; recruit; respiratory pathogen; response; superinfection; uptake

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.

抽象的 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，流感感染都会导致大量死亡，其中大多数是由于流感引起的 继发性细菌重复感染已被证明会增加对原发性流感感染的易感性。 通过改变肺部宿主免疫来继发耐甲氧西林金黄色葡萄球菌（MRSA）感染 反应并破坏肺上皮屏障，导致巨噬细胞发病率和死亡率增加， 肺部驻留病毒和招募到肺部的病毒，在吞噬时对解决超级感染很重要， 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， 而干扰素-(IFN)α/β在重复感染过程中的作用已得到很好的证实。 数据表明，III 型干扰素尚未主要在肺部进行研究。 IFNα/β参与原发性流感感染后的17型减毒，这可能表明IFNλ表现出 由于信号通路重叠而具有相似的抑制功能，尽管潜在的独特功能 肺细胞未解决。 我们实验室的初步数据表明，在重复感染期间给予外源性 IFNλ 可减少 嗜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。 我发现肺部巨噬细胞对 IFNλ 敏感，并且 IFNλ 信号传导会受损 在拟议的研究中，我将讨论吞噬作用和重复感染期间的 17 型免疫反应。 确定哪些骨髓亚群表达 IFNλ 受体 (IFNLR1)，并确定完整或破坏的 IFNλ 的情况 更具体地说，这些实验将广泛影响感染后的肺损伤和恢复。 确定 IFNλ 如何影响 MRSA 摄取以及超级免疫反应期间 17 型免疫反应的启动 IFNλ 给药已被认为具有治疗潜力，并且该提案的结果。 将阐明在重复感染期间使用 IFNλ 作为可能的治疗方法的潜在注意事项。 此外，证明 IFNλ 对骨髓细胞的影响可能适用于其他几种细胞。 观察到抗病毒干扰素反应的环境。