Host Molecules Regulating Neural Invasion of Zika Virus and Drug Repurposing Strategy

Abstract

Zika virus (ZIKV) is a mosquito-borne, single-stranded RNA virus belonging to the genus Flavivirus. Although ZIKV infection is usually known to exhibit mild clinical symptoms, intrauterine ZIKV infections have been associated with severe neurological manifestations, including microcephaly and Guillain Barre syndrome (GBS). Therefore, it is imperative to understand the mechanisms of ZIKV entry into the central nervous system (CNS) and its effect on brain cells. Several routes of neuro-invasion have been identified, among which blood-brain barrier (BBB) disruption is the commonest mode of access. The molecular receptors involved in viral entry remain unknown; with various proposed molecular ZIKV-host interactions including potential non-receptor mediated cellular entry. As ZIKV invade neuronal cells, they trigger neurotoxic mechanisms via cell-autonomous and non-cell autonomous pathways, resulting in neurogenesis dysfunction, viral replication, and cell death, all of which eventually lead to microcephaly. Together, our understanding of the biological mechanisms of ZIKV exposure would aid in the development of anti-ZIKV therapies targeting host cellular and/or viral components to combat ZIKV infection and its neurological manifestations. In this present work, we review the current understanding of ZIKV entry mechanisms into the CNS and its implications on the brain. We also highlight the status of the drug repurposing approach for the development of potential antiviral drugs against ZIKV.

Keywords: Trojan horse; autophagy; blood-brain barrier; drug repurposing; endoplasmic reticulum stress; inflammatory response; transcytosis; zika virus.

Figure 1

The proposed mechanisms of ZIKV invasion into the central nervous system (CNS). (1) Transcellular transport within endothelial cells of the BBB through infection or transcytosis mediated by ZIKV-induced degradation of Mfsd2a. (2) Paracellular trafficking of ZIKV across the blood–brain barrier (BBB) occurs through the upregulation of proinflammatory cytokines, chemokines, adhesion molecules and growth factors, and downregulation of tight junction proteins leading to alteration of the endothelial barrier integrity and permeability. (3) ZIKV-infected monocytes cross the BBB via the Trojan horse strategy. Once reach the CNS, ZIKV infects the brain cells, including astrocytes and microglial cells producing cytokines and chemokines leading to inflammation.

Figure 2

Zika virus-induced mitochondrial stress. ZIKV infection causes mitochondrial stress by altering its structure and metabolism to supply energy for viral replication through oxidative phosphorylation (OxPhos) pathway. This leads to an increase in reactive oxygen species (ROS) which causes DNA damage. Then the DNA damage response (DDR) is induced to activate repair pathways to monitor DNA damage.

Figure 3

ZIKV-induced endoplasmic reticulum (ER) stress and unfolded protein response. ZIKV infection causes structural changes of the ER as a result of accumulation of misfolded/unfolded ZIKV proteins and remodelling of the ER structure for viral RNA replication. The accumulation of misfolded/unfolded ZIKV proteins and the increase in ER protein-folding capacity triggers ER stress and activates the unfolded protein response (UPR), resulting in elevation of GRP78, calnexin, calreticulin, and protein disulfide isomerase (PDI). This is followed by initiation of several mechanisms such as global protein translation, stress granule assembly, reticulophagy and cytoplasmic vacuolisation. Zika virus proteins (capsid, NS3, NS2B/3 and NS4A proteins) has shown to, suppress SGs assembly, while NS2B/3 has shown to inhibit reticulophagy which facilitate continuous viral replication.