Abstract
Previous research demonstrated that the matrix protein (M) and glycoprotein (G) of attenuated rabies virus (RABV) strains are involved in the induction of host cell apoptosis. In this work, we show that wild-type (wt) RABV GD-SH-01 induces significantly greater apoptosis than the attenuated strain HEP-Flury. In order to identify the gene(s) accounting for this phenotype, five recombinant RABVs (rRABVs) were constructed by replacing each single gene of HEP-Flury with the corresponding gene of GD-SH-01. By using these rRABVs, we found that not only M and G, but also the phosphoprotein (P) plays an important role in inducing apoptosis. In order to figure out the different role of P gene in inducing apoptosis from the highly divergent background, another rRABV rGDSH-P, which carries the P gene of HEP-Flury in the background of the GD-SH-01 was generated. It was found that infection of NA cells with GD-SH-01 or the recombinant strain rHEP-shP, which carries P gene of GD-SH-01, induced significantly greater apoptosis than HEP-Flury or rGDSH-P in a caspase-dependent pathway that ultimately leads to the activation of the intrinsic apoptotic pathway, which is well characterized with the downregulation of bcl-2, the decrease of mitochondrial membrane potential, the release of mitochondrial cytochrome c, the activation of caspase-9 and caspase-3, and finally the cleavage of poly (ADP-ribose) polymerase. Our results imply that wt P from GD-SH-01 mediates this effect may partly by facilitating viral RNA synthesis but not by viral replication. In sum, we demonstrate a wt RABV strain GD-SH-01 to induce stronger apoptosis than an attenuated RABV HEP-Flury and propose that wt P from GD-SH-01 is involved in this process.
Highlights
The process of apoptosis is often referred to as programmed cell death and has first been described by John Kerr in 1972 (Kerr et al, 1972)
Previous research has demonstrated that attenuated rabies virus (RABV) may induce apoptosis, while wt RABV strains were apparently less able to do so (Thoulouze et al, 1997; Yan et al, 2001; Prehaud et al, 2003)
In order to identify which viral gene(s) account for the pro-apoptotic phenotype displayed by wt GD-SH-01, we compared this strain’s behavior with that of HEP-Flury and five recombinant RABVs (rRABVs)
Summary
The process of apoptosis is often referred to as programmed cell death and has first been described by John Kerr in 1972 (Kerr et al, 1972). According to our published work, wt RABV GD-SH-01 does induce greater apoptosis in mouse neuroblastoma (NA) cells than the attenuated RABV HEP-Flury (Peng et al, 2016) These results are not entirely consistent with findings reported in the past (Thoulouze et al, 1997; Yan et al, 2001), some reports do support our results (Ubol and Kasisith, 2000; Ubol et al, 2005; Yin et al, 2014). P of neither GD-SH-01 nor HEP-Flury was able to induce detectable apoptosis To our knowledge, this is the first study providing evidence that P gene of RABV plays a role in host cell apoptosis after viral infection. The results obtained in this study will extend our knowledge of RABV-induced apoptosis, which will help to understand the pathogenic mechanism of wt RABV since apoptosis are always closely correlated to viral pathogenicity and immunogenicity (Theerasurakarn and Ubol, 1998; Morimoto et al, 1999; Pulmanausahakul et al, 2001), and provide new perspectives to the pathogenic mechanism of virulent RABV
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