Death waits for no man--does it wait for a virus? How enteroviruses induce and control cell death

Abstract

Enteroviruses (EVs) are the most common human viral pathogens. They cause a variety of pathologies, including myocarditis and meningoencephalopathies, and have been linked to the onset of type I diabetes. These pathologies result from the death of cells in the myocardium, central nervous system, and pancreas, respectively. Understanding the role of EVs in inducing cell death is crucial to understanding the etiologies of these diverse pathologies. EVs both induce and delay host cell death, and their exquisite control of this balance is crucial for their success as human viral pathogens. Thus, EVs are tightly involved with cell death signaling pathways and interact with host cell signaling at multiple points. Here, we review the literature detailing the mechanisms of EV-induced cell death. We discuss the mechanisms by which EVs induce cell death, the signaling pathways involved in these pathways, and the strategies by which EVs antagonize cell death pathways. We also discuss the role of cell death in both the resulting pathology in the host and in the facilitation of viral spread.

Keywords: Apoptosis; Cell death; Coxsackievirus; Enterovirus; Poliovirus.

Figure 1. Mechanisms for the induction of apoptosis

Apoptosis can be induced through a number of mechanisms upon EV infection which include (1) release of ER-derived Ca²⁺ stores, (2) activation of the unfolded protein response (UPR), and (3) activation of stress activated protein kinases (SAPKs).

Figure 2. Mechanisms for the induction of apoptosis in EV-infected cells

The induction of apoptosis during an EV infection occurs in a number of ways including (1) the release of ER-derived Ca²⁺ stores by the PV virally-encoded virporin 2B, (2) the direct cleavage of host proteins by the virally-encoded cysteine protease 2A^pro and 3C^pro, (3) the detection of dsRNA produced as a replication intermediate by components associated with the innate immune system, and (4) direct binding of the EV capsid protein VP2 to the pro-apoptotic host cell component SIVA.

Figure 3. Mechanisms by which EVs antagonize host cell death pathways

EVs utilize a variety of diverse mechanisms to alter host cell death signaling which include (1) destruction of Ca²⁺ gradients by the production of virally-encoded viroporins such as 2B, (2) direct cleavage of pro-apoptotic host cell components by the virally-encoded 2A^pro and 3C^pro cysteine proteases, (3) activation of PI3K/Akt signaling pathways, and (4) internalization of TNFR by the virally-encoded 3A protein.