Centre Hospitalier Universitaire de Québec Research Center and Department of Molecular Medicine, Faculty of Medicine, Laval University, Quebec, Canada.
PLoS One. 2012;7(5):e36734. doi: 10.1371/journal.pone.0036734. Epub 2012 May 9.
Bacterial peptidoglycan-derived muramyl dipeptide (MDP) and derivatives have long-recognized antiviral properties but their mechanism of action remains unclear. In recent years, the pattern-recognition receptor NOD2 has been shown to mediate innate responses to MDP. Here, we show that MDP treatment of mice infected with Influenza A virus (IAV) significantly reduces mortality, viral load and pulmonary inflammation in a NOD2-dependent manner. Importantly, the induction of type I interferon (IFN) and CCL2 chemokine was markedly increased in the lungs following MDP treatment and correlated with a NOD2-dependent enhancement in circulating monocytes. Mechanistically, the protective effect of MDP could be explained by the NOD2-dependent transient increase in recruitment of Ly6C(high) "inflammatory" monocytes and, to a lesser extent, neutrophils to the lungs. Indeed, impairment in both Ly6C(high) monocyte recruitment and survival observed in infected Nod2-/- mice treated with MDP was recapitulated in mice deficient for the chemokine receptor CCR2 required for CCL2-mediated Ly6C(high) monocyte migration from the bone marrow into the lungs. MDP-induced pulmonary monocyte recruitment occurred normally in IAV-infected and MDP-treated Ips-1-/- mice. However, IPS-1 was required for improved survival upon MDP treatment. Finally, mycobacterial N-glycolyl MDP was more potent than N-acetyl MDP expressed by most bacteria at reducing viral burden while both forms of MDP restored pulmonary function following IAV challenge. Overall, our work sheds light on the antiviral mechanism of a clinically relevant bacterial-derived compound and identifies the NOD2 pathway as a potential therapeutic target against IAV.
细菌肽聚糖衍生的 muramyl dipeptide (MDP) 及其衍生物具有长期公认的抗病毒特性，但它们的作用机制仍不清楚。近年来，模式识别受体 NOD2 已被证明介导了对 MDP 的先天反应。在这里，我们表明，MDP 处理感染甲型流感病毒 (IAV) 的小鼠以依赖 NOD2 的方式显著降低死亡率、病毒载量和肺部炎症。重要的是，MDP 处理后肺部 I 型干扰素 (IFN) 和 CCL2 趋化因子的诱导明显增加，并且与循环单核细胞中依赖 NOD2 的增强相关。从机制上讲，MDP 的保护作用可以通过 NOD2 依赖性瞬态增加 Ly6C(high)“炎症”单核细胞的募集来解释，并且在较小程度上通过募集中性粒细胞来解释。事实上，在用 MDP 处理的感染 Nod2-/- 小鼠中观察到的 Ly6C(high)单核细胞募集和存活受损在缺乏 CCL2 介导的 Ly6C(high)单核细胞从骨髓迁移到肺部所需的趋化因子受体 CCR2 的小鼠中得到了重现。MDP 诱导的肺部单核细胞募集在 IAV 感染和 MDP 处理的 Ips-1-/- 小鼠中正常发生。然而，IPS-1 是在 MDP 治疗时提高存活率所必需的。最后，分枝杆菌 N- 糖基化 MDP 比大多数细菌表达的 N- 乙酰化 MDP 更有效降低病毒负担，而两种形式的 MDP 在 IAV 攻击后均恢复肺功能。总的来说，我们的工作阐明了一种临床相关细菌衍生化合物的抗病毒机制，并确定 NOD2 途径作为针对 IAV 的潜在治疗靶点。
