Stimulation of Immature Lung Macrophages with Intranasal Interferon Gamma in a Novel Neonatal Mouse Model of Respiratory Syncytial Virus Infection
Stimulation of Immature Lung Macrophages with Intranasal Interferon Gamma in a Novel Neonatal Mouse Model of Respiratory Syncytial Virus Infection
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DOI：
10.1371/journal.pone.0040499
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发表时间：
2012-07-06
期刊：
影响因子：
3.7
通讯作者：
Kolls, Jay K.
中科院分区：
文献类型：
--
作者：
Empey, Kerry M.;Orend, Jacob G.;Kolls, Jay K.
呼吸道合胞病毒（RSV）是婴儿细支气管炎和病毒性死亡的主要原因。气道中 CD8 T 细胞减少和可忽略的干扰素 γ (IFN γ) 与严重的婴儿 RSV 疾病有关，但肺泡巨噬细胞 (AM) 和中性粒细胞却大量存在。然而，根据我们目前对巨噬细胞功能异质性的理解，尚不清楚未成熟的 AM 是否会改善病毒清除率或在 IFN γ 缺陷的新生儿肺环境中导致炎症和气道阻塞。本研究的目的是确定新生儿 RSV 感染期间年龄依赖性 AM 表型，并使用 i.n 方法研究其与经典活化巨噬细胞 (CAM) 的分化。 IFN γ 在改善病毒清除方面的作用。新生和成年 BALB/cJ 小鼠感染 1x10(6) 噬菌斑形成单位 (PFU)/克 (g) RSV 19 系，并比较它们的 AM 反应。成年小鼠表现出快速而强烈的 CAM 反应，表现为主要组织相容性复合物 II 类 (MHC II)、CD86、CCR7 的增加和甘露糖受体 (MR) 的减少。新生小鼠表现出 CAM 反应延迟和降低，可能是由于无法检测到 IFN γ 的产生。与未治疗的对照相比，重组小鼠 IFN γ (rIFN γ) 鼻内 (i.n.) 治疗增加了新生儿 AM 上 CAM 标记物的表达，降低了病毒肺滴度，并改善了体重增加，且未检测到 CD4 或 CD8 T 细胞浸润增加。 J774A 的体外感染。带有 RSV 的 1 巨噬细胞诱导交替激活巨噬细胞 (AAM) 表型，然而，当巨噬细胞首先用 IFN γ 引发时，会诱导 CAM 表型，并且 RSV 扩散到相邻 Hep-2 细胞的数量减少。这些研究表明，新生儿 AM 对 RSV 感染的反应丰富且不成熟，但可以通过内源性刺激表达抗菌表型 CAM。 rIFN γ。
Respiratory syncytial virus (RSV) is the leading cause of bronchiolitis and viral death in infants. Reduced CD8 T-cells and negligible interferon gamma (IFN gamma) in the airway are associated with severe infant RSV disease, yet there is an abundance of alveolar macrophages (AM) and neutrophils. However, it is unclear, based on our current understanding of macrophage functional heterogeneity, if immature AM improve viral clearance or contribute to inflammation and airway obstruction in the IFN gamma-deficient neonatal lung environment. The aim of the current study was to define the age-dependent AM phenotype during neonatal RSV infection and investigate their differentiation to classically activated macrophages (CAM) using i.n. IFN gamma in the context of improving viral clearance. Neonatal and adult BALB/cJ mice were infected with 1x10(6) plaque forming units (PFU)/gram (g) RSV line 19 and their AM responses compared. Adult mice showed a rapid and robust CAM response, indicated by increases in major histocompatibility complex class II (MHC II), CD86, CCR7, and a reduction in mannose receptor (MR). Neonatal mice showed a delayed and reduced CAM response, likely due to undetectable IFN gamma production. Intranasal (i.n.) treatment with recombinant mouse IFN gamma (rIFN gamma) increased the expression of CAM markers on neonatal AM, reduced viral lung titers, and improved weight gain compared to untreated controls with no detectable increase in CD4 or CD8 T-cell infiltration. In vitro infection of J774A. 1 macrophages with RSV induced an alternatively activated macrophage (AAM) phenotype however, when macrophages were first primed with IFN gamma, a CAM phenotype was induced and RSV spread to adjacent Hep-2 cells was reduced. These studies demonstrate that the neonatal AM response to RSV infection is abundant and immature, but can be exogenously stimulated to express the antimicrobial phenotype, CAM, with i.n. rIFN gamma.