Abstract
Chinese giant salamander iridovirus (GSIV) is the causative pathogen of Chinese giant salamander (Andrias davidianus) iridovirosis, leading to severe infectious disease and huge economic losses. However, the infection mechanism by GSIV is far from clear. In this study, a Chinese giant salamander muscle (GSM) cell line is used to investigate the mechanism of cell death during GSIV infection. Microscopy observation and DNA ladder analysis revealed that DNA fragmentation happens during GSIV infection. Flow cytometry analysis showed that apoptotic cells in GSIV-infected cells were significantly higher than that in control cells. Caspase 8, 9, and 3 were activated in GSIV-infected cells compared with the uninfected cells. Consistently, mitochondria membrane potential (MMP) was significantly reduced, and cytochrome c was released into cytosol during GSIV infection. p53 expression increased at an early stage of GSIV infection and then slightly decreased late in infection. Furthermore, mRNA expression levels of pro-apoptotic genes participating in the extrinsic and intrinsic pathway were significantly up-regulated during GSIV infection, while those of anti-apoptotic genes were restrained in early infection and then rose in late infection. These results collectively indicate that GSIV induces GSM apoptotic cell death involving mitochondrial damage, caspases activation, p53 expression, and pro-apoptotic molecules up-regulation.
Highlights
Apoptosis, pyroptosis, and necroptosis are the three major ways of programmed cell death following virus infection, and apoptosis is the most extensively studied programmed cell death during the process [1,2,3]
Increased cell death was found in giant salamander iridovirus (GSIV)-infected cells at 12 and 24 h p.i., and at 48 h p.i., when apparent cytopathic effect arose. Droplet Digital PCR (ddPCR) analysis showed that the copies of GSIV major caspid protein (MCP) sharply increased from 6 h p.i. (Figure S1)
Ligand–ligand oligomerization of the receptors induce the intracellular assembly of death-inducing signaling complex (DISC), activation of caspase cascade that emanates from caspase 8 to effector caspases and nucleases, leading to apoptosis [1,19]
Summary
Pyroptosis, and necroptosis are the three major ways of programmed cell death following virus infection, and apoptosis is the most extensively studied programmed cell death during the process [1,2,3]. Apoptosis can be triggered by two fundamentally distinct signaling cascades, namely the extrinsic pathway (death adaptor pathway) and the intrinsic pathway (mitochondrial pathway) [5,6]. The extrinsic pathway is started by the ligand-induced oligomerization of specific cell surface receptors, and results in the activation of caspase 8 and caspase 3, leading to apoptosis [5]. The molecular mechanisms and signal pathways of virus-induced apoptosis have been disclosed in virus infection of mammal cells. Canine parvovirus NS1 can induce apoptosis proceeds through the intrinsic pathway which involves mitochondria, accumulation of reactive oxygen species, and activation of caspases [9]. In chronic hepatitis C virus infection, enhanced hepatocyte apoptosis and up-regulation of the death receptors have been described [10]. The molecular mechanism of viral infection in lower vertebrates like amphibians remains unclear
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