Abstract
The Rabbit Hemorrhagic Disease Virus (RHDV) induces a severe disease that fulfils many requirements of an animal model of fulminant hepatic failure. However, a better knowledge of molecular mechanisms contributing to liver damage is required, and it is unknown whether the RHDV induces liver autophagy and how it relates to apoptosis. In this study, we attempted to explore which signalling pathways were involved in the autophagic response induced by the RHDV and to characterize their role in the context of RHDV pathogenesis. Rabbits were infected with 2 × 104 hemmaglutination units of a RHDV isolate. The autophagic response was measured as presence of autophagic vesicles, LC3 staining, conversion of LC3-I to autophagosome-associated LC3-II and changes in expression of beclin-1, UVRAG, Atg5, Atg12, Atg16L1 and p62/SQSTM1. RHDV-triggered autophagy reached a maximum at 24 hours post-infection (hpi) and declined at 30 and 36 hpi. Phosphorylation of mTOR also augmented in early periods of infection and there was an increase in the expression of the endoplasmic reticulum chaperones BiP/GRP78, CHOP and GRP94. Apoptosis, measured as caspase-3 activity and expression of PARP-1, increased significantly at 30 and 36 hpi in parallel to the maximal expression of the RHDV capsid protein VP60. These data indicate that RHDV infection initiates a rapid autophagic response, perhaps in an attempt to protect liver, which associates to ER stress development and is independent from downregulation of the major autophagy suppressor mTOR. As the infection continues and the autophagic response declines, cells begin to exhibit apoptosis.
Highlights
The Rabbit Hemorrhagic Disease Virus (RHDV) is a positive-strand RNA virus, member of the Caliciviridae family, that causes in wild and domestic rabbits an acute highly fatal disease first reported three decades ago [1]
We have shown by data on animal survival, clinical features, histopathological findings, changes in blood chemistry and intracranial pressure monitoring that the RHD fulfils many of the requirements of an animal model of fulminant hepatic failure (FHF) [3]
The results from transmission electron microscopy (TEM) studies, LC3 hepatocyte labelling and LC3-II protein expression unequivocally demonstrate that the autophagy was induced at an early stage in rabbits infected with the RHDV
Summary
The Rabbit Hemorrhagic Disease Virus (RHDV) is a positive-strand RNA virus, member of the Caliciviridae family, that causes in wild and domestic rabbits an acute highly fatal disease first reported three decades ago [1]. The ubiquitin-like autophagy-related (Atg) is conjugated to Atg and forms a complex with Atg16L1, which is required in the elongation of the autophagosome membrane and determines its curvature. It has been reported that autophagy is activated upon ER stress as a defensive mechanism for survival [21], and it is known that some viruses stimulate signalling pathways from UPR to autophagy [22]. We have previously reported that RHDV leads to the activation of the different branches of the UPR [7] and induces apoptotic death in the last stages of the disease [5,6] It is unknown whether the RHDV induces autophagy in the liver of infected rabbits and how it relates to ER stress and apoptosis. We attempted to explore which signalling pathways were involved in the autophagic response induced by the RHDV and to characterize the role of autophagy in the context of RHDV pathogenesis
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