Dengue is the most prevalent mosquito-borne viral disease in the world. Globally, about half of the world’s population is now at risk of dengue with an estimated 100–400 million infections occurring each year. As of the writing of this story, 2,669 cases were reported in the United States this year; 1,797 spread through local transmission (all in Florida) and the other 872 were travel related. In addition, mosquito-borne viral infections are spreading due to climate change and no available treatments exist for this disease.
Dengue virus relies on the host cell’s machinery to produce the proteins encoded in its single-stranded RNA genome. This raises the question of whether dengue virus uses codons similar to that of its hosts—mosquitos and humans. This concept is called codon optimality: the effect that codon composition has on mRNA stability and translation level.
Now, research from the Stowers Institute for Medical Research in Kansas City, MO, has investigated the adaptation of virus genomes to the host optimality code. To do that, they used mosquito-borne dengue virus as a model. The findings uncovered strategies that dengue (and other viruses) use to replicate in their hosts, with the potential to aid in developing novel antiviral treatments and vaccines.
This work was published in Molecular Systems Biology in the paper, “Dengue virus preferentially uses human and mosquito nonoptimal codons.”
The Bazzini Lab at the Stowers Institute studies the codon optimality code in humans and other vertebrates. In this study, the researchers showed that dengue preferentially uses nonoptimal (destabilizing) codons and avoids codons that are defined as optimal (stabilizing) in either human or mosquito cells. This finding was contrary to the researchers’ original prediction.
“We were surprised to find that dengue virus preferentially uses the host’s less efficient codons, possibly as a strategy to evade an antiviral response by the host,” said Luciana Castellano, PhD, a postdoctoral researcher in the Bazzini lab.
More specifically, the group found that “human genes enriched in the codons preferentially and frequently used by dengue virus are upregulated during infection, and so is the tRNA decoding the nonoptimal and dengue virus preferentially used codon for arginine.” They found that “adaptation during single-host passaging in human or mosquito cells results in the selection of synonymous mutations toward dengue virus’s preferred nonoptimal codons that increase virus fitness.”
“Viruses accumulate mutations during infection of their hosts. We were surprised to find that mutations in the genome toward these less efficient codons increased dengue virus fitness in both mosquito and human cells,” said Ryan McNamara, a bioinformatics analyst in the Bazzini Lab.
The team analyzed hundreds of other human-infecting viruses and found that many of them, including HIV and SARS-CoV-2, preferentially use less efficient codons relative to humans, suggesting they have evolved an “inefficient” genome as a strategy to use host cell resources in a way that benefits the virus. The conserved preference among viruses has implications for understanding not only how viruses evolve but also how the host-pathogen relationship changes over time.
“Fundamentally, this work has altered how we think about the relationship between a virus and a host cell,” said Bazzini. “Now that we know what dengue and other viruses use when they infect our cells, we have clues for how we may be able to help prevent these deadly diseases.”
“As mosquitos are spreading to broader, more global regions, we need to start thinking very seriously about how to combat dengue and other mosquito-borne viral infections,” said Bazzini.
