The haemorrhagic disease virus (RHDV) is a non‐cultivable virus that promotes in rabbits an acute disease which accomplishes many characteristics of an animal model of fulminant hepatic failure (FHF). Beneficial effects of melatonin have been reported in RHDV‐infected rabbits. This study investigated whether protection against viral‐derived liver injury by melatonin is associated with modulation of mitophagy, innate immunity and clock signalling. Rabbits were experimentally infected with 2 × 10⁴ haemagglutination units of a RHDV isolate and killed at 18, 24 and 30 hours after infection (hpi). Melatonin (20 mg/kg body weight ip) was administered at 0, 12 and 24 hpi. RHDV infection induced mitophagy, with the presence of a high number of mitophagosomes in hepatocytes and increased expression of mitophagy genes. Greater expression of main innate immune intermediaries and inflammasome components was also found in livers with RHDV‐induced FHF. Both mitophagy and innate immunity activation was significantly hindered by melatonin. FHF induction also elicited an early dysregulation in clock signalling, and melatonin was able to prevent such circadian disruption. Our study discloses novel molecular routes contributing to RHDV‐induced damage progression and supports the potential of melatonin as a promising therapeutic option in human FHF.

中文翻译：

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褪黑素在病毒性暴发性肝功能衰竭模型中调节线粒体，先天免疫和昼夜节律。

出血性疾病病毒（RHDV）是一种不可培养的病毒，可在兔中促进急性疾病，该疾病实现了暴发性肝衰竭（FHF）动物模型的许多特征。褪黑激素的有益作用已在受RHDV感染的兔子中报道。这项研究调查了褪黑素对病毒性肝损伤的保护作用是否与线粒体的调节，先天免疫和时钟信号有关。实验性地用2×10 ⁴感染兔子RHDV的血凝单位，在感染后18、24和30小时被杀死。分别在0、12和24 hpi服用褪黑激素（20 mg / kg体重腹膜内注射）。RHDV感染诱导了线粒体吞噬，肝细胞中存在大量的线粒体，并且线粒体基因的表达增加。在RHDV诱导的FHF的肝脏中也发现了主要的先天免疫中间物和炎性体成分的更高表达。褪黑素显着阻碍了线粒体和先天免疫的激活。FHF诱导还引起了时钟信号的早期失调，褪黑激素能够预防这种昼夜节律紊乱。我们的研究揭示了有助于RHDV诱导的损伤进程的新型分子途径，并支持褪黑激素作为人类FHF的有希望的治疗选择的潜力。