Apoptosis during ZIKA Virus Infection: Too Soon or Too Late?

Abstract

Cell death by apoptosis is a major cellular response in the control of tissue homeostasis and as a defense mechanism in the case of cellular aggression such as an infection. Cell self-destruction is part of antiviral responses, aimed at limiting the spread of a virus. Although it may contribute to the deleterious effects in infectious pathology, apoptosis remains a key mechanism for viral clearance and the resolution of infection. The control mechanisms of cell death processes by viruses have been extensively studied. Apoptosis can be triggered by different viral determinants through different pathways as a result of virally induced cell stresses and innate immune responses. Zika virus (ZIKV) induces Zika disease in humans, which has caused severe neurological forms, birth defects, and microcephaly in newborns during the last epidemics. ZIKV also surprised by revealing an ability to persist in the genital tract and in semen, thus being sexually transmitted. Mechanisms of diverting antiviral responses such as the interferon response, the role of cytopathic effects and apoptosis in the etiology of the disease have been widely studied and debated. In this review, we examined the interplay between ZIKV infection of different cell types and apoptosis and how the virus deals with this cellular response. We illustrate a duality in the effects of ZIKV-controlled apoptosis, depending on whether it occurs too early or too late, respectively, in neuropathogenesis, or in long-term viral persistence. We further discuss a prospective role for apoptosis in ZIKV-related therapies, and the use of ZIKV as an oncolytic agent.

Keywords: ZIKV; Zika virus; apoptosis; cell death.

Figure 1

The different pathways of apoptosis. Apoptosis can follow several pathways, depending on the signals integrated by the cell and the respective influence of the mobilized pro- and anti-apoptotic factors. The extrinsic pathway is induced by external death signals such as TNFα and mediated by death receptors (FAS, DR4 expressed on the cell surface. The intrinsic pathway is induced by internal stimuli such as DNA damage, oxidative stress, or intracellular parasites. Apoptosis could also be activated by unresolved endoplasmic reticulum stress (ER stress) and unfolded protein response (UPR) through C/EBP HOmologous Protein (CHOP) [15,16,17,18,19,20,21,22]. Viruses such as BHV, DENV, WNV, JEV, and HSV (in red) can induce apoptosis by the activation of different pathways [23,24,25,26,27,28,29,30,31,32,33,34,35].

Figure 2

Zika virus structure and life cycle. (A) Scheme of Zika virus genome and structure. Zika virus genome encodes 10 viral proteins, three structural, and seven non-structural. 5′ and 3′ UTR refer to untranslated regions [65]. (B) ZIKV binds its specific receptors and is subsequently internalized into the target cell via clathrin-mediated endocytosis (1). Viral RNA is released into the cytoplasm following virus fusion with the endosomal membrane and capsid disassembly (2). Upon release, positive-sense RNA is translated into a polypeptide incorporated in the endoplasmic reticulum (ER) membrane and cleaved by proteases into structural and non-structural proteins (3,4). It will also be transcribed into negative-sense RNA that will serve as a template for RNA replication that takes place in ER vesicle packets (5,6). Viral proteins are accumulated and structured at the level of the ER (7). Virus assembly, budding, and maturation then occur in the ER-Golgi intermediate compartment (ERGIC) and in the Golgi apparatus, respectively (8,9). New viruses are released by exocytosis (10). Adapted from Lebeau et al. [66].

Figure 3

Zika virus controls apoptosis. ZIKV acts on anti-apoptotic factors such as Bcl-2 or Bcl-xL mainly through an effect mediated by the non-structural proteins. ZIKV controls CHOP activity during UPR, limiting its pro-apoptotic activity [92]. DsRNA/TLR3 induced apoptosis is controlled by ZIKV through NS2B/3 [82]. ZIKV also stimulates the expression of pro survival factors such as fibroblast growth factor 2 (FGF2) [88,93].

Figure 4

Zika as an oncolytic agent, pros and cons. ZIKV has natural tropism for neurons but its replication is counteracted by antiviral pathways. Tumor cells overexpress receptors for viral entry, have a high metabolism that efficiently supports ZIKV replication, and have frequent defects in antiviral pathways. These natural capacities enhance viral infection (1). To further improve its tropism toward the tumor, ZIKV could be modified to specifically target tumor cell receptors or to be more dependent on the tumor’s singular properties (2). Delayed apoptosis induced by ZIKV replication allows for a more immunogenic cell death, which can turn an immunosuppressive tumor microenvironment into an immunoactivating one (3). Delayed apoptosis also promotes transgene expression allowing for more efficient delivery of therapeutics (4).

Figure 5

Too soon or too late, graphical abstract. ZIKV-related apoptosis is ambivalent. On one hand, the virus transmission to the central nervous system via microglia and astrocytes induces early apoptosis of neuroprogenitor cells. This leads to a set of symptoms and defects grouped under the term of ZIKV congenital syndrome. On the other hand, ZIKV has been shown to persist for a while in infected organisms due to delayed apoptosis. Persisting in the genital tract could lead to sexual transmission that is unusual for an arbovirus.