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.
Highlights
The Flaviviridae family, Flavivirus genus, consists of a variety of viruses transmitted by blood-feeding arthropod species, several of which represent emergent or reemergent pathogens including Zika (ZIKV), Dengue (DENV), Yellow Fever (YFV), Japanese Encephalitis (JEV), and West Nile (WNV) viruses
The predicted Protein-Protein Interactions (PPIs) are complemented with the annotation of the proteins which have been quantified in different human cells upon ZIKV infection
The analysis of the ZIKV-human interactome reveals that this virus shares some of the targets and strategies with other Flavivirus to infect human host cells
Summary
The Flaviviridae family, Flavivirus genus, consists of a variety of viruses transmitted by blood-feeding arthropod species, several of which represent emergent or reemergent pathogens including Zika (ZIKV), Dengue (DENV), Yellow Fever (YFV), Japanese Encephalitis (JEV), and West Nile (WNV) viruses. A successful innate immune response by the host depends on the efficient detection of the invading pathogen. Flavivirus use their structural glycoproteins to attach to the host cell, interacting with several receptors, which trigger endocytosis pathways. Sequence comparisons of the E glycoprotein of ZIKV with the other members of the Flaviviridae family indicate an unusual degree of variability including glycosylation within the ZIKV strains [12]. These differences in glycosylation may determine a characteristic affinity for human target proteins
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