Abstract
ABSTRACT Zika virus (ZIKV) is a historically neglected mosquito-borne flavivirus that has caused recent epidemics in the western hemisphere. ZIKV has been associated with severe symptoms including infant microcephaly and Guillain-Barré syndrome, stimulating interest in understanding factors governing ZIKV infection. Heat shock protein 70 (Hsp70) has been shown to be an infection factor for multiple viruses, leading us to investigate the role of Hsp70 in the ZIKV infection process. ZIKV infection induced Hsp70 expression in host cells 48-h post-infection. Inducing Hsp70 expression in mammalian cells increased ZIKV production, whereas inhibiting Hsp70 activity reduced ZIKV viral RNA production and virion release from the cell. Hsp70 was localized both on the cell surface where it could interact with ZIKV during the initial stages of the infection process, and intracellularly where it localized with viral RNA. Blocking cell surface-localized Hsp70 using antibodies decreased ZIKV cell infection rates and production of infectious virus particles, as did competition with recombinant Hsp70 protein. Overall, Hsp70 was found to play a functional role in both the pre- and post-ZIKV infection processes affecting viral entry, replication, and egress. Understanding the interactions between Hsp70 and ZIKV may lead to novel therapeutics for ZIKV infection.
Highlights
Zika virus (ZIKV) is a historically neglected mosquitoborne flavivirus first isolated in 1947 that, until recently, typically resulted in a handful of documented cases with mild clinical phenotypes
We investigated the effect of ZIKV infection on the expression of Heat shock protein 70 (Hsp70)
The decrease in viral titre was as high as 3 logs for pre-treatment and 4 logs for post-treatment samples compared to the control, indicating that Hsp70 may have a role both at entry and post-entry levels of ZIKV infection
Summary
Zika virus (ZIKV) is a historically neglected mosquitoborne flavivirus first isolated in 1947 that, until recently, typically resulted in a handful of documented cases with mild clinical phenotypes. The occurrence of severe clinical outcomes for fetuses and pregnant women in this outbreak has stimulated interest in determining the factors governing ZIKV infection [8,9]. The binding of a virus to specific cell surface receptor(s) is a critical step for cellular tropism and an important determinant of pathogenesis [10]. Heat shock protein 70 (Hsp70) has been shown to be one such factor for multiple viruses including dengue virus (DV), Japanese encephalitis virus (JEV), Hazara virus, and rotavirus, where it may act directly as a receptor or indirectly to help attach and gather viruses on the cell surface to facilitate interactions with specific high-affinity receptors [16–19]. We demonstrate that Hsp is an important factor in multiple stages of the ZIKV cell infection process including viral entry, replication, and egress. Understanding the interactions between Hsp and ZIKV may lead to novel therapeutics for ZIKV infection
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