Department of Veterinary Preventive Medicine, College of Veterinary Medicine, The Ohio State University, Columbus, OH, USA.
Department of Physiology and Cell Biology, College of Medicine, The Ohio State University, Columbus, OH, USA.
Virology. 2021 Jul;559:111-119. doi: 10.1016/j.virol.2021.03.008. Epub 2021 Apr 6.
Influenza A virus (IAV) infection alters lung epithelial cell metabolism in vitro by promoting a glycolytic shift. We hypothesized that this shift benefits the virus rather than the host and that inhibition of glycolysis would improve infection outcomes. A/WSN/33 IAV-inoculated C57BL/6 mice were treated daily from 1 day post-inoculation (d.p.i.) with 2-deoxy-d-glucose (2-DG) to inhibit glycolysis and with the pyruvate dehydrogenase kinase (PDK) inhibitor dichloroacetate (DCA) to promote flux through the TCA cycle. To block OXPHOS, mice were treated every other day from 1 d.p.i. with the Complex I inhibitor rotenone (ROT). 2-DG significantly decreased nocturnal activity, reduced respiratory exchange ratios, worsened hypoxemia, exacerbated lung dysfunction, and increased humoral inflammation at 6 d.p.i. DCA and ROT treatment normalized oxygenation and airway resistance and attenuated IAV-induced pulmonary edema, histopathology, and nitrotyrosine formation. None of the treatments altered viral replication. These data suggest that a shift to glycolysis is host-protective in influenza.
甲型流感病毒（IAV）感染通过促进糖酵解途径改变体外肺上皮细胞代谢。我们假设这种转变对病毒有利而不是宿主有利，抑制糖酵解将改善感染结果。从感染后 1 天（d.p.i.）开始，用 2-脱氧-D-葡萄糖（2-DG）每天抑制糖酵解，用丙酮酸脱氢酶激酶（PDK）抑制剂二氯乙酸（DCA）促进三羧酸循环通量，对 A/WSN/33 IAV 感染的 C57BL/6 小鼠进行处理。为了阻断 OXPHOS，从感染后 1 天开始每隔一天用复合物 I 抑制剂鱼藤酮（ROT）处理小鼠。2-DG 显著降低了夜间活动，降低了呼吸交换率，加重了低氧血症，使肺功能障碍恶化，并在 6 天增加了体液炎症。DCA 和 ROT 治疗使氧合和气道阻力正常化，并减轻了 IAV 诱导的肺水肿、组织病理学和硝基酪氨酸形成。这些治疗都没有改变病毒复制。这些数据表明，流感中糖酵解的转变对宿主是有保护作用的。
