Autophagy in Zika Virus Infection: A Possible Therapeutic Target to Counteract Viral Replication

Abstract

Zika virus (ZIKV) still constitutes a public health concern, however, no vaccines or therapies are currently approved for treatment. A fundamental process involved in ZIKV infection is autophagy, a cellular catabolic pathway delivering cytoplasmic cargo to the lysosome for degradation-considered as a primordial form of innate immunity against invading microorganisms. ZIKV is thought to inhibit the Akt-mTOR signaling pathway, which causes aberrant activation of autophagy promoting viral replication and propagation. It is therefore appealing to study the role of autophagic molecular effectors during viral infection to identify potential targets for anti-ZIKV therapeutic intervention.

Keywords: Akt-mTOR; Zika virus; autophagy; innate immunity; therapeutic targets.

Figure 1

Mechanisms involved in Zika virus-host cell interactions. The binding of ZIKV structural glycoproteins to cellular entry receptors triggers viral internalization through clathrin-dependent endocytosis (1). The endosomal lumen’s acidic pH induces conformational changes of viral surface glycoproteins thus allowing the fusion of viral envelope with endosomal membrane, causing the release of viral RNA into the cytosol (2). Viral RNA is then translated into viral proteins (3). Immature viral particles assemble within the endoplasmic reticulum (ER) (4), and vesicle trafficking enables the transition of ZIKV from the ER to the Golgi network (5). ZIKV then passes through the cisternae of the Golgi apparatus and promotes viral maturation (6). Mature ZIKV particles are delivered and liberated into the extracellular environment (7).

Figure 2

The role of autophagy during innate and adaptive immune responses against invading microorganisms. As a fundamental component of the innate immune response, selective autophagy degrades invading pathogens principally through ubiquitin-signaling. Ubiquinated pathogens are recognized by sequestosome-1/p62-like receptors (SLRs), which are involved in creating a molecular bridge between 1A/1B light-chain 3 (LC3) recruited on ER membranes and the ubiquinated microbial components, thus promoting their enclosure into the autophagosomes of target molecules. The subsequent fusion of autophagosomes with lysosomes leads to pathogen degradation and direct elimination. These vesicles containing exogenous antigenic peptides, derived from lysosome degradation, fuse with major histocompatibility complex class II (MHC-II) loading-compartments. After loading on MHC-II, the peptides are transported to the cell surface in order to induce the stimulation of a CD4⁺ T-cell anti-viral adaptive immune response.

Figure 3

The role of autophagy in the regulation of inflammatory responses against invading pathogens. Microbial pathogen-associated molecular patterns (PAMPs) are recognized by toll-like receptors (TLRs) located on the plasma membrane or in endosomal compartments (1). The recognition of activated TLRs by adaptor proteins Myd88 or TRIF (2), activates TLR signaling pathways (3), involved in the activation of transcription factors Nf-KB, IRF3/7, and API-1 that then translocate to the nucleus for the induction of INF and pro-inflammatory cytokines transcription (4). The promotion of autophagosome formation is induced in a Myd88- or TRIF-dependent manner (5), and leads to the regulation of inflammasome activation and secretion of pro-inflammatory cytokines, through mechanisms that remain not completely understood (6), and to the delivery of PAMPs to TLR-containing vesicles to limit viral replication (7). Besides promoting pro-inflammatory activities, autophagy also serves as an impediment on the magnitude of the host’s antiviral reaction. Indeed, autophagy-related proteins (Atg12 and Atg5) might serve as a break for the pro-inflammatory response induce by TLRs (8).

Figure 4

Deregulation of autophagy during Dengue virus infection. During DENV infection, autophagy has pro-viral activity. The induction of autophagy by DENV (1) upregulates autophagosomes formation (2) that fuse with endosomes to form amphisomes (3), virus-induced compartments in which DENV actively replicates (4). Accumulating autophagosomes stimulate lipid metabolism (5) leading to the liberation of fatty acids and energy to sustain viral replication (6).

Figure 5

Deregulation of autophagy during ZIKV infection. Following ZIKV internalization, release of genomic material from endosomes and translation of viral RNA (1), NS4A and NS4B facilitate the curvature of ER membranes to promote assembly of immature viral particles (2) and inactivate the mTORC-pathway (3) by limiting Akt phosphorylation, thus inducing autophagy (5). The upregulation in autophagosome formation (5) activates secretory autophagy (6) with subsequent liberation of mature ZIKV particles (7).

Figure 6

The role of autophagy in ZIKV infection. The ZIKV entry mechanism is mediated by a wide range of receptors. After membrane fusion, viral genetic material is released into the cytoplasm and translated into proteins. The formation of vesicle packets causes ER stress and triggers autophagy. Chloroquine acts by increasing the pH within the endosomes, inhibiting membrane fusion and exocytosis by secretory autophagy.

Figure 7

Compound testing and drug design to limit autophagy: a possible approach to counteract ZIKV infection. Different compounds possess the ability to modulate crucial steps for autophagy progression. Considering the fundamental role of autophagy in promoting viral replication and advancement of infection, the testing of molecules known to act on autophagy might be essential to identify and select candidates to test for anti-ZIKV activity.