New Targets forZikaVirus Determined by Human-Viral Interactomic: A Bioinformatics Approach

Abstract

Identifying ZIKV factors interfering with human host pathways represents a major challenge in understanding ZIKV tropism and pathogenesis. The integration of proteomic, gene expression and Protein-Protein Interactions (PPIs) established between ZIKV and human host proteins predicted by the OralInt algorithm identified 1898 interactions with medium or high score (≥0.7). Targets implicated in vesicular traffic and docking were identified. New receptors involved in endocytosis pathways as ZIKV entry targets, using both clathrin-dependent (17 receptors) and independent (10 receptors) pathways, are described. New targets used by the ZIKV to undermine the host's antiviral immune response are proposed based on predicted interactions established between the virus and host cell receptors and/or proteins with an effector or signaling role in the immune response such as IFN receptors and TLR. Complement and cytokines are proposed as extracellular potential interacting partners of the secreted form of NS1 ZIKV protein. Altogether, in this article, 18 new human targets for structural and nonstructural ZIKV proteins are proposed. These results are of great relevance for the understanding of viral pathogenesis and consequently the development of preventive (vaccines) and therapeutic targets for ZIKV infection management.

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

“…Viral structural glycoproteins, in particular envelope E glycoprotein, mediate binding to cellular receptors, thereby triggering endocytotic pathways. These interactions between cellular receptors and glycoproteins allow ZIKV to infect specific cellular types including fibroblasts, immature dendritic cells, epidermal keratinocytes, and stem-cell-derived human neural progenitor cells [ 7 ]. The uptake of viral particles occurs primarily through clathrin-dependent endocytosis.…”

“…This completes the entry process, which implies the delivery of viral RNA into the cytoplasm of the host cell. The positive-sense RNA is translated into a polyprotein, which is subsequently cleaved to release structural and NS proteins [ 7 ]. Cellular compartments such as the endoplasmic reticulum (ER) and the Golgi apparatus, seem to be crucial for viral replication and propagation.…”

“…Second, immature viral particles are assembled within the ER and virions traffic through the Golgi network for particle maturation prior to the release from the infected cell. Mature particles are then delivered into the extracellular environment where they are ready to commence a new infectious life cycle ( Figure 1 ) [ 7 , 9 ].…”

The Neurobiology of Zika Virus: New Models, New Challenges

“…It has been suggested that its invasion relies on a more complex interaction of AXL receptor, since its experimental ablation does not prevent the viral invasion ( Wells et al, 2016 ). Indeed, ZIKV would be able to infect different types of neuronal cells through the exploitation of multiple cell surface receptors and cytosolic components ( Esteves et al, 2017 ). This impairs multiple cellular processes, causing cell death, inflammatory response, disrupting the normal biological development ( Rosa-Fernandes et al, 2019 ).…”

“…IFN signaling depends on the interactions with entry cell receptors, such as AXL (a cell surface TAM-family receptor) ( Lemke, 2013 ; Meertens et al, 2017 ). AXL is pivotal for flaviviruses and is expressed in several cells, such as some placental cells, astrocytes, microglia, oligodendrocytes, human radial glia and NPCs ( Li et al, 2016 ; Akkermann et al, 2017 ; Esteves et al, 2017 ; Meertens et al, 2017 ). Its precise role remains uncertain; it could act as an entry factor for ZIKV endocytosis ( Meertens et al, 2017 ; Ojha et al, 2019 ) or antagonize type I IFN signaling ( Chen et al, 2018 ).…”