Modulation of apoptosis by caprine herpesvirus 1 infection in a neuronal cell line

Abstract

Caprine herpesvirus type 1 (CpHV-1), like other members of the alpha subfamily of herpesviruses, establishes latent infections in trigeminal ganglion neurons. Our groups previously demonstrated that CpHV-1 induces apoptosis in goat peripheral blood mononuclear cells and in an epithelial bovine cell line, but the ability of CpHV-1 to induce apoptosis in neuronal cells remains unexplored. In this report, the susceptibility of Neuro 2A cells to infection by CpHV-1 was examined. Following infection of cultured cells with CpHV-1, expression of cell death genes was evaluated using real-time PCR and Western blot assays. Analysis of virus-infected cells revealed activation of caspase-8, a marker for the extrinsic pathway of apoptosis, and caspase-9, a marker for the intrinsic pathway of apoptosis at 12 and 24 h post-infection. Significant increase in the levels of cleaved caspase-3 was also observed at the acme of cytopathic effect at 24 h post-infection. In particular, at 3 and 6 h post-infection, several proapototic genes were under-expressed. At 12 h post-infection several proapototic genes such as caspases, TNF, Cd70, and Traf1 were over expressed while Bcl2a1a, Fadd, and TNF genes were underexpressed. In conclusion, the simultaneous activation of caspase-8 and caspase-9 suggests that CpHV-1 can trigger the death-receptor pathway and the mitochondrial pathway separately and in parallel. Our findings are significant because this is the first published study showing the effect of CpHV-1 infection in neuronal cells in terms of gene expression and apoptosis modulation.

Bovine herpesviruses induce different cell death forms in neuronal and glial-derived tumor cell cultures

“…Most of alphaherpesviruses have been shown to induce cell destruction caused by apoptosis (Christensen et al 2011;Cymerys et al 2012;Delhon et al 2002;Geiser et al 2008;Hood et al 2003;Montagnaro et al 2013). Although different apoptotic forms have been described induced by BHV1 and 5 infection (Brenner et al 2012;Cardoso et al 2012Cardoso et al , 2015Delhon et al 2002;Garcia et al 2013;Geiser et al 2008;Ladelfa et al 2013;Silva-Frade et al 2010Zhu et al 2016), this particular mechanism remains unknown.…”

“…The correlation coefficient (r) was calculated according to the Spearman analysis and p < 0.005 was considered significant 2010). In fact, Neuro2a cells have been described as a model of neuronal death studies upon infection with varicella-zoster virus (Christensen et al 2011), equid herpesvirus 1 (Cymerys et al 2012), and caprine herpesvirus 1 (Montagnaro et al 2013). All these studies revealed susceptibility of neuronal tumor cells to animal alphaherpesviruses and their deleterious effects.…”

RETRACTED ARTICLE: Comparative analysis of the replication of bovine herpesvirus 1 (BHV1) and BHV5 in bovine-derived neuron-like cells

“…Recently, it has been shown that caprine herpesvirus 1 (CpHV-1) infecting a neuronal cell line triggered deathreceptor and mitochondrial pathways separately and in parallel [20]. However, murine neurons infected with equine herpesvirus 1 (EHV1) showed no changes, and cells survived for more than eight weeks in culture [4].…”

“…Virus replication in neural tissue is accompanied by neuronal degeneration, but the exact mechanism of this process remains unknown. One possibility could be the induction of programmed cell death, which has already been demonstrated for other alphaherpesviruses [4,14,16,17,20]. Studies in vitro have shown that, following BoHV1 infection of cultured neurons obtained from rabbit ganglionic tissue, hallmarks of apoptosis such as chromatin condensation, DNA fragmentation and membrane blebbing are detected [8].…”

Programmed cell death: the battlefield between the host and alpha-herpesviruses and a potential avenue for cancer treatment

“…A series of Bcl-2 protein family members, including Bax, Bak, Bcl-2, Bcl-xl, Mcl-1, Bid, and Bim, can destroy the mitochondrial membrane potential (MMP). Cytochrome c (Cyt-c) is then released from the mitochondria into the cytoplasm and combines with pro-caspase-9 and Apaf-1 to form a complex to activate caspase-9, which subsequently activates the downstream molecules caspase-3 (Figure 1 ) [ 5 , 29 – 31 ].…”