Abstract

Both mosquito species-specific differences and virus strain -specific differences impact vector competence. Previous results in our laboratory with individual populations of N. American mosquitoes support studies suggesting Aedes aegypti are more competent than Ae. albopictus for American Zika virus (ZIKV) strains and demonstrate that U.S. Ae. albopictus have higher competence for an ancestral Asian ZIKV strain. A982V, an amino acid substitution in the NS1 gene acquired prior to the American outbreak, has been shown to increase competence in Ae. aegypti. We hypothesized that variability in the NS1 could therefore contribute to species-specific differences and developed a reverse genetics system based on a 2016 ZIKV isolate from Honduras (ZIKV-WTic) to evaluate the phenotypic correlates of individual amino acid substitutions. In addition to A982V, we evaluated G894A, which was acquired during circulation in the Americas. Reversion of 982 and 894 to ancestral residues increased infectivity, transmissibility and viral loads in Ae. albopictus but had no effect on competence or replication in Ae. aegypti. In addition, while host cell-specific differences in NS1 secretion were measured, with significantly higher secretion in mammalian cells relative to mosquito cells, strain-specific differences in secretion were not detected, despite previous reports. These results demonstrate that individual mutations in NS1 can influence competence in a species-specific manner independent of differences in NS1 secretion and further indicate that ancestral NS1 residues confer increased competence in Ae. albopictus. Lastly, experimental infections of Ifnar1-/- mice demonstrated that these NS1 substitutions can influence viral replication in the host and, specifically, that G894A could represent a compensatory change following a fitness loss from A982V with some viral genetic backgrounds. Together these data suggest a possible role for epistatic interactions in ZIKV fitness in invertebrate and vertebrate hosts and demonstrate that strains with increased transmission potential in U.S. Ae. albopictus could emerge.

Highlights

  • Zika virus (ZIKV; Flaviviridae, flavivirus) was first isolated in Uganda in 1947 [1] and became a public health concern following an outbreak on the islands of Yap in 2007 [2]

  • It has been shown that an amino acid substitution in the NS1 gene acquired prior to the American outbreak confers increased infectivity in Ae. aegypti

  • To investigate the role of the ZIKV NS1 in competence of both Ae. aegypti and Ae. albopictus we utilized reverse genetics to revert to the ancestral NS1 residues and characterized the resultant mutant strains

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Summary

Introduction

Zika virus (ZIKV; Flaviviridae, flavivirus) was first isolated in Uganda in 1947 [1] and became a public health concern following an outbreak on the islands of Yap in 2007 [2]. Autochthonous transmission of ZIKV was first identified in the Western Hemisphere in Brazil in May 2015 [4] but isolates from 2014 from Haiti have since been identified [5]. ZIKV subsequently expanded throughout Latin America and into the U.S and, infections have decreased dramatically since 2017, there were over 800,000 suspected or confirmed cases occurring in at least 48 Western countries from 2015 to 2018 [6]. Sequence analyses indicate that there are two distinct phylogenetic lineages of ZIKV; African and Asian [7,8]. It has been shown that a virus belonging to the Asian lineage was the source of the outbreak in the Americas [9]

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