Division of Critical Care Medicine, Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611;
Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL 60611.
J Immunol. 2018 Apr 1;200(7):2391-2404. doi: 10.4049/jimmunol.1701543. Epub 2018 Feb 14.
Healthy children are more likely to die of influenza A virus (IAV) infection than healthy adults. However, little is known about the mechanisms underlying the impact of young age on the development of life-threatening IAV infection. We report increased mortality in juvenile mice compared with adult mice at each infectious dose of IAV. Juvenile mice had sustained elevation of type I IFNs and persistent NLRP3 inflammasome activation in the lungs, both of which were independent of viral titer. Juvenile mice, but not adult mice, had increased MCP-1 levels that remained high even after viral clearance. Importantly, continued production of MCP-1 was associated with persistent recruitment of monocytes to the lungs and prolonged elevation of inflammatory cytokines. Transcriptional signatures of recruited monocytes to the juvenile and adult IAV-infected lungs were assessed by RNA-seq. Genes associated with a proinflammatory signature were upregulated in the juvenile monocytes compared with adult monocytes. Depletion of monocytes with anti-CCR2 Ab decreased type I IFN secretion, NLRP3 inflammasome activation, and lung injury in juvenile mice. This suggests an exaggerated inflammatory response mediated by increased recruitment of monocytes to the lung, and not an inability to control viral replication, is responsible for severe IAV infection in juvenile mice. This study provides insight into severe IAV infection in juveniles and identifies key inflammatory monocytes that may be central to pediatric acute lung injury secondary to IAV.
健康儿童死于甲型流感病毒（IAV）感染的可能性高于健康成年人。然而，对于年龄对危及生命的 IAV 感染发展的影响的机制知之甚少。我们报告说，在每个 IAV 感染剂量下，幼年小鼠的死亡率均高于成年小鼠。幼年小鼠的 I 型 IFNs 和 NLRP3 炎性小体持续激活，肺部持续升高，这两者均与病毒滴度无关。幼年小鼠而非成年小鼠的 MCP-1 水平升高，即使在清除病毒后仍保持高水平。重要的是，MCP-1 的持续产生与单核细胞向肺部的持续募集和炎症细胞因子的持续升高有关。通过 RNA-seq 评估了招募到幼年和成年 IAV 感染肺部的单核细胞的转录特征。与成年单核细胞相比，幼年单核细胞中与促炎特征相关的基因上调。用抗 CCR2 Ab 耗尽单核细胞可减少幼年小鼠的 I 型 IFN 分泌、NLRP3 炎性小体激活和肺损伤。这表明，炎症反应的过度加剧是由单核细胞向肺部的募集增加引起的，而不是控制病毒复制的能力下降，这是幼年小鼠发生严重 IAV 感染的原因。这项研究为幼年患者严重 IAV 感染提供了新的见解，并确定了关键的炎症性单核细胞，这可能是 IAV 引起的小儿急性肺损伤的关键。
