Functional Genomics and Immunologic Tools: The Impact of Viral and Host Genetic Variations on the Outcome of Zika Virus Infection.

Sang-Im Yun,Irina Polejaeva,Christopher Davies,Kenneth White,Jordan Frank,Justin Julander,Byung-Hak Song,Aaron Olsen,Young-Min Lee

doi:10.3390/v10080422

Abstract

Zika virus (ZIKV) causes no-to-mild symptoms or severe neurological disorders. To investigate the importance of viral and host genetic variations in determining ZIKV infection outcomes, we created three full-length infectious cDNA clones as bacterial artificial chromosomes for each of three spatiotemporally distinct and genetically divergent ZIKVs: MR-766 (Uganda, 1947), P6-740 (Malaysia, 1966), and PRVABC-59 (Puerto Rico, 2015). Using the three molecularly cloned ZIKVs, together with 13 ZIKV region-specific polyclonal antibodies covering nearly the entire viral protein-coding region, we made three conceptual advances: (i) We created a comprehensive genome-wide portrait of ZIKV gene products and their related species, with several previously undescribed gene products identified in the case of all three molecularly cloned ZIKVs. (ii) We found that ZIKV has a broad cell tropism in vitro, being capable of establishing productive infection in 16 of 17 animal cell lines from 12 different species, although its growth kinetics varied depending on both the specific virus strain and host cell line. More importantly, we identified one ZIKV-non-susceptible bovine cell line that has a block in viral entry but fully supports the subsequent post-entry steps. (iii) We showed that in mice, the three molecularly cloned ZIKVs differ in their neuropathogenicity, depending on the particular combination of viral and host genetic backgrounds, as well as in the presence or absence of type I/II interferon signaling. Overall, our findings demonstrate the impact of viral and host genetic variations on the replication kinetics and neuropathogenicity of ZIKV and provide multiple avenues for developing and testing medical countermeasures against ZIKV.

Highlights

Discovered in Uganda in 1947 in a febrile rhesus macaque [1], Zika virus (ZIKV) is a medically important flavivirus [2] related to Japanese encephalitis (JEV), West Nile (WNV), dengue, and yellow fever viruses [3]
In all three strains of ZIKV, we found that the genomic RNA is 10,807 nt long, with a single open reading frame (ORF) of 10,272 nt flanked by a 106 or 107 nt 50 non-coding regions (NCRs) and a 428 or 429 nt 30 NCR
We demonstrated that using pBac/P6-740, the infectivity of its RNA transcripts was decreased by ~4 logs to a barely detectable level (55–105 plaque-forming units (PFU)/μg), with a single C9804 →U substitution replacing a His with Tyr at position 713 of the viral NS5 protein (Figure S1A,B)

Summary

Introduction

Discovered in Uganda in 1947 in a febrile rhesus macaque [1], Zika virus (ZIKV) is a medically important flavivirus [2] related to Japanese encephalitis (JEV), West Nile (WNV), dengue, and yellow fever viruses [3]. It was confined within an equatorial belt running from Africa to Asia, Viruses 2018, 10, 422; doi:10.3390/v10080422 www.mdpi.com/journal/viruses. Pacific Island of Yap [5,6]. Since it has spread eastward across the Pacific Ocean, invading. Serious concerns have been raised over links to congenital neurological malformations (e.g., microcephaly) and severe neurological complications (e.g., Guillain–Barré syndrome) [17,18]

Methods

Results

Conclusion