Department of Medicine, Department of Microbiology & Immunology, Department of Pathology, McGill International TB Centre, McGill University Health Centre and Research Institute, Meakins-Christie Laboratories, 3626 St. Urbain Street, Montreal, Quebec H2X 2P2, Canada.
Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, 1015 Arlington Street, Winnipeg, MB R3E 3R2, Canada.
Immunity. 2014 Apr 17;40(4):554-68. doi: 10.1016/j.immuni.2014.02.013. Epub 2014 Apr 10.
Aspirin gained tremendous popularity during the 1918 Spanish Influenza virus pandemic, 50 years prior to the demonstration of their inhibitory action on prostaglandins. Here, we show that during influenza A virus (IAV) infection, prostaglandin E2 (PGE2) was upregulated, which led to the inhibition of type I interferon (IFN) production and apoptosis in macrophages, thereby causing an increase in virus replication. This inhibitory role of PGE2 was not limited to innate immunity, because both antigen presentation and T cell mediated immunity were also suppressed. Targeted PGE2 suppression via genetic ablation of microsomal prostaglandin E-synthase 1 (mPGES-1) or by the pharmacological inhibition of PGE2 receptors EP2 and EP4 substantially improved survival against lethal IAV infection whereas PGE2 administration reversed this phenotype. These data demonstrate that the mPGES-1-PGE2 pathway is targeted by IAV to evade host type I IFN-dependent antiviral immunity. We propose that specific inhibition of PGE2 signaling might serve as a treatment for IAV.
阿司匹林在 1918 年西班牙流感病毒大流行期间获得了巨大的普及，这比它们抑制前列腺素作用的证明早了 50 年。在这里，我们表明，在甲型流感病毒（IAV）感染期间，前列腺素 E2（PGE2）上调，导致巨噬细胞中 I 型干扰素（IFN）的产生和凋亡受到抑制，从而导致病毒复制增加。PGE2 的这种抑制作用不仅局限于先天免疫，因为抗原呈递和 T 细胞介导的免疫也受到抑制。通过靶向消除微粒体前列腺素 E 合酶 1（mPGES-1）或通过药理学抑制 PGE2 受体 EP2 和 EP4 来抑制 PGE2，可显著提高对致死性 IAV 感染的存活率，而 PGE2 给药则逆转了这种表型。这些数据表明，IAV 靶向 mPGES-1-PGE2 途径以逃避宿主 I 型 IFN 依赖性抗病毒免疫。我们提出，特异性抑制 PGE2 信号可能是治疗 IAV 的一种方法。
