African and Asian Zika Virus Isolates Display Phenotypic Differences Both In Vitro and In Vivo

Abstract

Zika virus (ZIKV) is a mosquito-borne member of the genus that has emerged since 2007 to cause outbreaks in Africa, Asia, Oceania, and most recently, in the Americas. Here, we used an isolate history as well as genetic and phylogenetic analyses to characterize three low-passage isolates representing African (ArD 41525) and Asian (CPC-0740, SV0127-14) lineages to investigate the potential phenotypic differences in vitro and in vivo. The African isolate displayed a large plaque phenotype (∼3-4 mm) on Vero and HEK-293 cells, whereas the Asian isolates either exhibited a small plaque phenotype (∼1-2 mm) or did not produce any plaques. In multistep replication kinetics in nine different vertebrate and insect cell lines, the African isolate consistently displayed faster replication kinetics and yielded ∼10- to 10,000-fold higher peak virus titers (infectious or RNA copies) compared with the Asian isolates. Oral exposure of mosquitoes with the African isolate yielded higher infection and dissemination rates compared with the Asian isolates. Infection of mice with the African isolate produced a uniformly fatal disease, whereas infection with the Asian isolates produced either a delay in time-to-death or a significantly lower mortality rate. Last, the African isolate was> 10,000-fold more virulent than the Asian isolates in an interferon type I antibody blockade mouse model. These data demonstrate substantial phenotypic differences between low-passage African and Asian isolates both in vitro and in vivo and warrant further investigation. They also highlight the need for basic characterization of ZIKV isolates, as the utilization of the uncharacterized isolates could have consequences for animal model and therapeutic/vaccine development.

Infection with a Brazilian isolate of Zika virus generates RIG‐I stimulatory RNA and the viral NS5 protein blocks type I IFN induction and signaling

“…Indeed, recent studies have reported that ZIKV NS5 proteins from African and French Polynesian isolates antagonize IFNAR signaling by targeting STAT2 for degradation . However, NS5 and other ZIKV proteins from virus strains associated with the latest outbreak in Brazil have not yet been analyzed in this context, which is important given that Zika virus isolates differ significantly in in vivo and in vitro infection settings . Additionally, ZIKV infection has been suggested to prevent STAT1 and STAT2 phosphorylation .…”

High transmissibility and fetal pathogenicity of recent Zika virus strains from the African lineage

“…The lack of human outbreaks associated with the African lineage of ZIKV until now 27 is paradoxical because a large majority of experimental studies have found a higher transmissibility and pathogenicity of the African ZIKV strains relative to their Asian counterparts [28][29][30][31][32][33][34] . We hypothesized that this discrepancy could have reflected the lack of recent, low-passage African strains available for experimental studies.…”

“…Surprisingly, a growing body of experimental evidence, both in vitro and in vivo, points towards a higher transmissibility and pathogenicity of the African ZIKV strains compared to their Asian counterparts. African ZIKV strains typically cause more productive and more lethal infections than Asian strains in cell culture [28][29][30][31][32][33][34] , they are more transmissible by mosquitoes [35][36][37][38][39] and they are associated with more severe pathology in adult mice and mouse embryos 34,[40][41][42][43][44][45][46][47][48] . A few studies, however, reported evidence supporting the opposite conclusion in non-human primates [49][50][51] , various cell types 52,53 and mosquitoes 47 .…”

A Zika Virus Primary Isolate Induces Neuroinflammation, Compromises the Blood-Brain Barrier, and Upregulates CXCL12 in Adult Macaques

“…African and Asian ZIKV strains are associated with phenotypic differences in both in vitro replication and in vivo pathogenesis (28–31). The Rio-U1 ZIKV stock used in this study was a primary stock isolated from a Brazilian patient and is not adapted to cell culture.…”