Virus uncoating is required for apoptosis induction in cultured mammalian cells infected with African horse sickness virus

Abstract

Infection of cultured mammalian cells with African horse sickness virus (AHSV) is known to induce cell death. To date, the trigger(s) of this response, the apoptotic pathways activated during AHSV infection and the functional consequences of apoptosis on the virus replication cycle have yet to be characterized. This study demonstrated that extracellular treatment of BHK-21 cells with both of the AHSV4 outer capsid proteins, VP2 and VP5, was sufficient to trigger apoptosis. Whether steps in AHSV4 replication subsequent to viral attachment were required for AHSV4-induced apoptosis was also investigated. Apoptosis was induced in BHK-21 cells infected with UV-inactivated AHSV4 and in ribavirin-treated cells infected with AHSV4. However, both AHSV4-and VP2/VP5-stimulated apoptotic responses were inhibited in the presence of the endosomal acidification inhibitors ammonium chloride and chloroquine. These results indicated that uncoating of AHSV4 virions, but not viral transcription or subsequent steps in viral replication, was required for AHSV4 to induce apoptosis in BHK-21 cells. Furthermore, this study showed that both the extrinsic (caspase-8) and intrinsic (caspase-9) apoptotic pathways were induced following AHSV4 infection. The inhibition of caspase activity in AHSV4-infected cells did not diminish AHSV4 replication, but reduced the release and dissemination of progeny viral particles. Taken together, the data indicated that uncoating of AHSV virions was required for apoptosis induction, and that apoptosis enhanced virus spread and release.

The Culicoides sonorensis inhibitor of apoptosis 1 protein protects mammalian cells from apoptosis induced by infection with African horse sickness virus and bluetongue virus

“…Notably, biochemical data indicated that CsIAP1 is an inhibitor of caspase-9, the initiator caspase of the intrinsic apoptotic pathway. Thus, the inability of CsIAP1 expression to completely block virus-induced apoptosis may be ascribed to the ability of BTV and AHSV to induce both the intrinsic and extrinsic apoptotic pathways that exist within mammalian cells (Stewart and Roy, 2010;Vermaak and Theron, 2015). In the experimental system used in this study, apoptosis could therefore still be induced via the extrinsic pathway despite suppression of the intrinsic apoptosis pathway by CsIAP1.…”

“…In contrast, virus-infected mammalian cell cultures show strong CPE that correlates with the amount of apoptosis in the cells (Mortola et al, 2004;Stassen et al, 2012). Although apoptotic pathways induced in mammalian cells by orbivirus infections have been characterized (Stewart and Roy, 2010;Vermaak and Theron, 2015), there is a paucity of information regarding apoptosis and apoptosis regulation in Culicoides midges and their derived cell lines.…”

Apoptosis versus survival of African horse sickness virus serotype 4-infected horse peripheral blood mononuclear cells

“…This showed that apoptosis and the clearance of virus-infected apoptotic cells are conceivably crucial host defence mechanisms to limit virus replication and spread. (Vermaak and Theron, 2015). On the other hand, apoptosis occurs very rapidly, taking between 2-3 h from induction to completion (Elmore, 2007).…”

Review on the Biology of African Horse Sickness Virus and Its Vector

“…Apoptosis, pyroptosis and necroptosis are also mechanisms used by the cell after sensing virus infection in order to restrict replication and virus spread [38]. But African horse sickness virus cause apoptosis during entry of the virus into the cytosol [87].…”