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症代表了全球死亡的主要原因。 每年，影响都会导致大量死亡，其中大多数是复杂的 次生细菌超级感染。原发性影响力感染已被证明增加了对 通过改变肺部宿主免疫，二甲氧西林金黄色葡萄球菌（MRSA）感染 反应并破坏肺上皮屏障，导致发病率和死亡率增加。巨噬细胞， 肺部居民和被招募到肺部的人都在超级感染的解决方案中很重要，因为他们吞噬了， 降解并呈现细菌抗原对适应性免疫细胞的抗原，最终导致17型细胞的激活， 促进病原体清除率。虽然超级感染过程中干扰素（IFN）α/β的作用一直很好 表征，在肺部的背景下，III型IFN并未像广泛的研究。数据显示 IFNα/β参与原发性影响后感染后17型衰减，这可能表明IFNλ表现出 尽管有重叠的信号通路引起的相似抑制功能，尽管在唯一功能上的潜力 肺部细胞尚未解决。 我们的实验室有初步数据表明，超级感染期间的外源IFNλ会减少 中性粒细胞和单核细胞衍生的细胞的细菌摄取，但受影响的特定细胞子集尚不清楚。 我假设肺居民巨噬细胞对IFNλ敏感，而IFNλ信号会损害 超级感染期间的吞噬作用和17型免疫响应。在拟议的研究中，我将 确定哪种髓样子集表达IFNλ受体（IFNLR1），并确定IFNλ的完整或破坏 信号广泛影响感染后的肺损伤和分辨率。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型免疫响应的主动性 感染。 IFNλ给药已被考虑用于治疗潜力和该提案的结果 将阐明潜在的警告，以在超级感染期间使用IFNλ作为可能的治疗方法。 此外，表明IFNλ对髓样细胞的影响可能适用于其他几个 观察到抗病毒干扰反应的设置。