Abstract
Dengue virus (DENV) infection of an individual human or mosquito host produces a dynamic population of closely-related sequences. This intra-host genetic diversity is thought to offer an advantage for arboviruses to adapt as they cycle between two very different host species, but it remains poorly characterized. To track changes in viral intra-host genetic diversity during horizontal transmission, we infected Aedes aegypti mosquitoes by allowing them to feed on DENV2-infected patients. We then performed whole-genome deep-sequencing of human- and matched mosquito-derived DENV samples on the Illumina platform and used a sensitive variant-caller to detect single nucleotide variants (SNVs) within each sample. >90% of SNVs were lost upon transition from human to mosquito, as well as from mosquito abdomen to salivary glands. Levels of viral diversity were maintained, however, by the regeneration of new SNVs at each stage of transmission. We further show that SNVs maintained across transmission stages were transmitted as a unit of two at maximum, suggesting the presence of numerous variant genomes carrying only one or two SNVs each. We also present evidence for differences in selection pressures between human and mosquito hosts, particularly on the structural and NS1 genes. This analysis provides insights into how population drops during transmission shape RNA virus genetic diversity, has direct implications for virus evolution, and illustrates the value of high-coverage, whole-genome next-generation sequencing for understanding viral intra-host genetic diversity.
Highlights
With 3.6 billion people at risk and nearly 400 million infections annually [1,2], dengue has become the most important mosquito-borne viral disease affecting humans today
To study the impact of human-to-mosquito transmission on Dengue virus (DENV) populations, we allowed mosquitoes to feed directly on patients with acute dengue infections, deep-sequenced DENV populations from patient plasma samples and from the abdomens and salivary glands of corresponding mosquitoes. These matched samples allowed us to estimate the size of the population drop that occurs during establishment of infection in the mosquito, track changes in viral intra-host variant repertoires at different stages in transmission, and investigate the possibility of host-specific immune selection pressures acting on the virus population
These novel insights improve our understanding of DENV population dynamics during horizontal transmission
Summary
With 3.6 billion people at risk and nearly 400 million infections annually [1,2], dengue has become the most important mosquito-borne viral disease affecting humans today. Dengue virus (DENV) is a positive-sense, single-stranded RNA virus of the family Flaviviridae, genus Flavivirus. DENV is transmitted between humans by the mosquitoes Aedes aegypti and Aedes albopictus. Which acquire the virus by taking a bloodmeal from an infected human. DENV first infects and replicates in the mosquito midgut epithelium. It subsequently disseminates through the hemolymph to infect other organs such as the fat body and trachea, reaching the salivary glands, where it is secreted into mosquito saliva and injected into a human host during a subsequent blood-feeding event [3]
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