Alveolar macrophages support interferon gamma-mediated viral clearance in RSV-infected neonatal mice.
Alveolar macrophages support interferon gamma-mediated viral clearance in RSV-infected neonatal mice.
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DOI：
10.1186/s12931-015-0282-7
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发表时间：
2015-10-05
影响因子：
5.8
通讯作者：
Empey KM
中科院分区：
文献类型：
--
作者：
Eichinger KM;Egaña L;Orend JG;Resetar E;Anderson KB;Patel R;Empey KM
呼吸道合胞病毒（RSV）感染期间干扰素γ（IFNγ）产生不足与新生小鼠和人类的病毒清除延长和疾病严重程度增加相关。我们先前表明，在观察到T淋巴细胞募集或活化之前，鼻内递送IFNγ显著增强新生儿肺中RSV的清除，表明病毒清除的先天免疫机制。我们进一步表明，肺泡巨噬细胞占主导地位的RSV感染的新生儿气道相对于成人，与人类新生儿尸检数据一致。因此，本研究的目的是确定新生儿肺泡巨噬细胞在IFNγ介导的RSV清除中的作用。采用氯膦酸盐脂质体、流式细胞术、病毒空斑试验和组织学检查肺泡巨噬细胞（AM）的作用和鼻内IFNγ在RSV感染的新生Balb/c小鼠中的作用。使用空斑试验通过病毒滴度定量测定AM耗竭的功能结果。通过测量体重增加减少来评估疾病。RSV感染时AM的活化具有年龄依赖性，并与IFNγ暴露密切相关。较高剂量的IFNγ更有效地刺激AM激活并加速RSV清除，而不会显着影响体重增加。AM的存在与RSV清除率的提高独立相关，而AM耗竭（而非IFNγ暴露）显著损害了RSV感染新生儿的体重增加。我们在这里首次表明，IFNγ对新生儿RSV清除至关重要，并且它部分依赖于肺泡巨噬细胞（AM）的有效病毒清除作用。病毒负荷的早期减少可能对脆弱的出生后发育的肺部环境产生深远的短期和长期免疫影响。正在进行研究，以阐明与新生儿气道发育中RSV早期清除与延迟清除相关的病理效应。
Poor interferon gamma (IFNγ) production during respiratory syncytial virus (RSV) is associated with prolonged viral clearance and increased disease severity in neonatal mice and humans. We previously showed that intra-nasal delivery of IFNγ significantly enhances RSV clearance from neonatal lungs prior to observed T-lymphocyte recruitment or activation, suggesting an innate immune mechanism of viral clearance. We further showed that alveolar macrophages dominate the RSV-infected neonatal airways relative to adults, consistent with human neonatal autopsy data. Therefore, the goal of this work was to determine the role of neonatal alveolar macrophages in IFNγ-mediated RSV clearance. Clodronate liposomes, flow cytometry, viral plaque assays, and histology were used to examine the role of alveolar macrophages (AMs) and the effects of intra-nasal IFNγ in RSV infected neonatal Balb/c mice. The functional outcomes of AM depletion were determined quantitatively by viral titers using plaque assay. Illness was assessed by measuring reduced weight gain. AM activation during RSV infection was age-dependent and correlated tightly with IFNγ exposure. Higher doses of IFNγ more efficiently stimulated AM activation and expedited RSV clearance without significantly affecting weight gain. The presence of AMs were independently associated with improved RSV clearance, whereas AM depletion but not IFNγ exposure, significantly impaired weight gain in RSV-infected neonates. We show here for the first time, that IFNγ is critical for neonatal RSV clearance and that it depends, in part, on alveolar macrophages (AMs) for efficient viral clearing effects. Early reductions in viral burden are likely to have profound short- and long-term immune effects in the vulnerable post-natally developing lung environment. Studies are ongoing to elucidate the pathologic effects associated with early versus delayed RSV clearance in developing neonatal airways.