Abstract
Most vertebrate RNA viruses show pervasive suppression of CpG and UpA dinucleotides, closely resembling the dinucleotide composition of host cell transcriptomes. In contrast, CpG suppression is absent in both invertebrate mRNA and RNA viruses that exclusively infect arthropods. Arthropod-borne (arbo) viruses are transmitted between vertebrate hosts by invertebrate vectors and thus encounter potentially conflicting evolutionary pressures in the different cytoplasmic environments. Using a newly developed Zika virus (ZIKV) model, we have investigated how demands for CpG suppression in vertebrate cells can be reconciled with potentially quite different compositional requirements in invertebrates and how this affects ZIKV replication and transmission. Mutant viruses with synonymously elevated CpG or UpA dinucleotide frequencies showed attenuated replication in vertebrate cell lines, which was rescued by knockout of the zinc-finger antiviral protein (ZAP). Conversely, in mosquito cells, ZIKV mutants with elevated CpG dinucleotide frequencies showed substantially enhanced replication compared to wild type. Host-driven effects on virus replication attenuation and enhancement were even more apparent in mouse and mosquito models. Infections with CpG- or UpA-high ZIKV mutants in mice did not cause typical ZIKV-induced tissue damage and completely protected mice during subsequent challenge with wild-type virus, which demonstrates their potential as live-attenuated vaccines. In contrast, the CpG-high mutants displayed enhanced replication in Aedes aegypti mosquitoes and a larger proportion of mosquitoes carried infectious virus in their saliva. These findings show that mosquito cells are also capable of discriminating RNA based on dinucleotide composition. However, the evolutionary pressure on the CpG dinucleotides of viral genomes in arthropod vectors directly opposes the pressure present in vertebrate host cells, which provides evidence that an adaptive compromise is required for arbovirus transmission. This suggests that the genome composition of arbo flaviviruses is crucial to maintain the balance between high-level replication in the vertebrate host and persistent replication in the mosquito vector.
Highlights
Arthropod-borne viruses are transmitted between vertebrate hosts by invertebrate arthropod vectors such as mosquitoes, ticks, biting midges, and sand flies
To compare the CpG and UpA dinucleotide usage between different flaviviruses, the ratio of CpG and UpA dinucleotide frequencies from full-length flavivirus genome sequences were plotted as the observed over the expected (O/E) frequencies (Fig 1A, large data points)
The motivation for this study was the evident difference in CpG dinucleotide representation in the genomes of RNA viruses infecting vertebrates compared to those infecting insects (Fig 1) [5,13,14,31]
Summary
Arthropod-borne viruses (arboviruses) are transmitted between vertebrate hosts by invertebrate arthropod vectors such as mosquitoes, ticks, biting midges, and sand flies. Transmission of arboviruses requires active virus replication in 2 evolutionary distant hosts that are separated by more than 500 million years of evolution [1]. Arboviruses encounter divergent cellular and molecular environments, exemplified by the different antiviral responses that vertebrate hosts and invertebrate vectors rely on to cope with viral infections. Vertebrate animals possess a plethora of innate and adaptive antiviral immune responses [2], while invertebrates largely rely on RNA interference (RNAi) to control viral infections [3,4]. The transmission cycle of arboviruses places them in 2 distinct intracellular environments with dissimilar adaptive pressures for replication and evasion of host antiviral responses (reviewed in [5]). How arboviruses are able to thrive while continuously alternating between these distinct cellular environments remains an intriguing research topic [6]
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