Key Laboratory of Animal Epidemiology of Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University, Beijing, China.
Beijing Key Laboratory for Prevention and Control of Infectious Diseases in Livestock and Poultry, Institute of Animal Husbandry and Veterinary Medicine, Beijing Academy of Agriculture and Forestry Sciences, Beijing, China.
PLoS Pathog. 2023 May 18;19(5):e1011406. doi: 10.1371/journal.ppat.1011406. eCollection 2023 May.
Influenza A virus (IAV) H1N1 infection is a constant threat to human health and it remains so due to the lack of an effective treatment. Since melatonin is a potent antioxidant and anti-inflammatory molecule with anti-viral action, in the present study we used melatonin to protect against H1N1 infection under in vitro and in vivo conditions. The death rate of the H1N1-infected mice was negatively associated with the nose and lung tissue local melatonin levels but not with serum melatonin concentrations. The H1N1-infected AANAT-/- melatonin-deficient mice had a significantly higher death rate than that of the WT mice and melatonin administration significantly reduced the death rate. All evidence confirmed the protective effects of melatonin against H1N1 infection. Further study identified that the mast cells were the primary targets of melatonin action, i.e., melatonin suppresses the mast cell activation caused by H1N1 infection. The molecular mechanisms involved melatonin down-regulation of gene expression for the HIF-1 pathway and inhibition of proinflammatory cytokine release from mast cells; this resulted in a reduction in the migration and activation of the macrophages and neutrophils in the lung tissue. This pathway was mediated by melatonin receptor 2 (MT2) since the MT2 specific antagonist 4P-PDOT significantly blocked the effects of melatonin on mast cell activation. Via targeting mast cells, melatonin suppressed apoptosis of alveolar epithelial cells and the lung injury caused by H1N1 infection. The findings provide a novel mechanism to protect against the H1N1-induced pulmonary injury, which may better facilitate the progress of new strategies to fight H1N1 infection or other IAV viral infections.
甲型流感病毒（IAV）H1N1 感染是对人类健康的持续威胁，由于缺乏有效的治疗方法，这种威胁仍然存在。由于褪黑素是一种具有抗病毒作用的强效抗氧化剂和抗炎分子，因此在本研究中，我们使用褪黑素在体外和体内条件下预防 H1N1 感染。感染 H1N1 的小鼠的死亡率与鼻和肺组织局部褪黑素水平呈负相关，但与血清褪黑素浓度无关。与 WT 小鼠相比，感染 AANAT-/-褪黑素缺乏型小鼠的死亡率明显更高，而褪黑素给药可显著降低死亡率。所有证据均证实了褪黑素对 H1N1 感染的保护作用。进一步的研究确定，肥大细胞是褪黑素作用的主要靶标，即褪黑素抑制 H1N1 感染引起的肥大细胞活化。所涉及的分子机制包括褪黑素下调 HIF-1 通路的基因表达，并抑制肥大细胞中促炎细胞因子的释放；这导致肺组织中巨噬细胞和中性粒细胞的迁移和活化减少。该途径由褪黑素受体 2（MT2）介导，因为 MT2 特异性拮抗剂 4P-PDOT 可显著阻断褪黑素对肥大细胞活化的作用。通过靶向肥大细胞，褪黑素抑制了肺泡上皮细胞的凋亡和 H1N1 感染引起的肺损伤。这些发现提供了一种保护免受 H1N1 诱导的肺损伤的新机制，这可能更有利于推进针对 H1N1 感染或其他 IAV 病毒感染的新策略的进展。
