How do viruses control mitochondria-mediated apoptosis?

Abstract

There is no doubt that viruses require cells to successfully reproduce and effectively infect the next host. The question is what is the fate of the infected cells? All eukaryotic cells can "sense" viral infections and exhibit defence strategies to oppose viral replication and spread. This often leads to the elimination of the infected cells by programmed cell death or apoptosis. This "sacrifice" of infected cells represents the most primordial response of multicellular organisms to viruses. Subverting host cell apoptosis, at least for some time, is therefore a crucial strategy of viruses to ensure their replication, the production of essential viral proteins, virus assembly and the spreading to new hosts. For that reason many viruses harbor apoptosis inhibitory genes, which once inside infected cells are expressed to circumvent apoptosis induction during the virus reproduction phase. On the other hand, viruses can take advantage of stimulating apoptosis to (i) facilitate shedding and hence dissemination, (ii) to prevent infected cells from presenting viral antigens to the immune system or (iii) to kill non-infected bystander and immune cells which would limit viral propagation. Hence the decision whether an infected host cell undergoes apoptosis or not depends on virus type and pathogenicity, its capacity to oppose antiviral responses of the infected cells and/or to evade any attack from immune cells. Viral genomes have therefore been adapted throughout evolution to satisfy the need of a particular virus to induce or inhibit apoptosis during its life cycle. Here we review the different strategies used by viruses to interfere with the two major apoptosis as well as with the innate immune signaling pathways in mammalian cells. We will focus on the intrinsic mitochondrial pathway and discuss new ideas about how particular viruses could activately engage mitochondria to induce apoptosis of their host.

Enterovirus 71 2B Induces Cell Apoptosis by Directly Inducing the Conformational Activation of the Proapoptotic Protein Bax

“…Members of the Bcl-2 family are key regulators of apoptosis via the mitochondrial pathway. The proapoptotic proteins Bax and Bak are the most downstream activator molecules known for Cyt c release (51,52). Thus, it is not surprising that mitochondria are directly targeted by numerous virus proteins to modulate apoptosis.…”

Getting the “Kill” into “Shock and Kill”: Strategies to Eliminate Latent HIV

“…Additionally, increases in the anti-apoptotic protein Bcl-2 results in elevated levels of anti-oxidant molecules like glutathione and thioredoxin, thereby protecting latently infected cells from oxidative stress-induced apoptosis (Aillet et al, 1998). The XIAP protein, which inhibits the protease activity of caspase-3, -7 and -9 (Berro et al, 2007; Neumann et al, 2015), is also increased in latently infected cells compared to uninfected cells (Berro et al, 2007) to favour cell survival. Finally, inhibition of other pro-apoptotic cellular proteins in latently infected cells may also be involved.…”

Extreme Competence: Keystone Hosts of Infections

“…Among other activities, mitochondria regulate innate immune activation, adaptive immune cell differentiation [53], and detection of viruses through pathogen recognition receptors [54]. Some viruses and Toxoplasma gondii can hijack mitochondria to modulate host apoptosis [55] or meet parasite nutrient needs [56]. Collectively, we expect that major advances in understanding EC will occur when host defenses are studied in an organismal manner [57,58].…”