Researchers Expose How Mosquito-Borne Viruses Infect Hosts
Dengue and other viruses preferentially use a host’s less efficient codons, possibly to evade an antiviral response.

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As mosquitoes continue to spread across the globe, so do the infections they carry. In June, the Centers for Disease Control and Prevention (CDC) issued a health alert notifying the public of an increased risk of dengue virus infections in the United States.
Now, research from the Stowers Institute for Medical Research offers new hope in the search for novel antiviral treatments and vaccines against dengue viral infections.
Published in the journal Molecular Systems Biology, the study uncovered surprising strategies for how dengue and hundreds of other viruses replicate in their hosts, with the potential to target these strategies to diminish viral replication.
Dengue takes advantage of non-optimal host codons
Using the mosquito-borne dengue virus as a model, the researchers discovered that viruses tend to preferentially use particular codons to encode their proteins, and these tend to be “non-optimal” codons in both humans and mosquitoes.
What is a codon?
A codon is a sequence of three consecutive nucleotides in a DNA or RNA molecule that codes for a specific amino acid. Codons that signal the start or end of translation are called start or stop codons.
“We analyzed the genomes of hundreds of human viruses, including dengue virus, and calculated the frequency of each codon in the genome to investigate which codons these viruses prefer to use,” Dr. Ariel Bazzini, associate investigator at the Stowers Institute for Medical Research, told Technology Networks. “We found that hundreds of viruses preferentially use less optimal codons suggesting that the choice is conserved and therefore important for virus infections.”
The dengue genome consists of single-stranded RNA. RNA viruses have a dependence on the host cells' translation machinery to synthesize the proteins it requires for propagation.
“The genetic code is degenerative, this means that there are more codons (the 3-nucleotide ‘words’ read by the ribosome) to encode for the 20 amino acids that humans, mosquitoes and viruses use,” explained Bazzini. “Those codons encoding for the same amino acid are called synonymous or silent, but we know that those codons are not silent from the regulatory point of view, some are optimal and some not.”
Synonymous codons have individual properties that can impact a cell’s efficiency for manufacturing proteins as well as the stability of RNA. A synonymous codon can be efficient and optimal in one species but inefficient and non-optimal in another.
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Subscribe for FREEThe researchers had predicted that the dengue virus would use synonymous codons that are deemed more optimal in their mosquito and human hosts. “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, predoctoral researcher at the Stowers Institute for Medical Research.
The researchers went on to analyze 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.
“We still do not know how the virus benefits from using these less optimal codons,” said Bazzini. “We have shown that at least some tRNA are differentially regulated during dengue virus infection, so it is possible that the virus or the host are affecting those to modulate the level of translation as well as the mRNA stability of the genes enriched in those codons.”
These findings have implications for our existing understanding of how viruses evolve and how the relationship between a virus and host cell changes over time.
Combating a rising global threat
Dengue is the most prevalent mosquito-borne viral disease in the world, causing an estimated 390 million infections each year. “Climate change and the lack of consistent efforts to control the spreading of the mosquitoes are some of the main reasons why there is an increasing risk of spread of the dengue epidemic and other mosquito-borne viral diseases to new areas,” explained Bazzini.
The researchers hope that an improved understanding of how dengue and other viruses infect host cells may provide clues for preventing these deadly diseases.
“On the one hand, attenuated viruses have been used as vaccines after changing codons to weaken the virus to avoid infection while still causing an immune response. Recoding viral genes based on codon optimality might help in the design of vaccines,” said Bazzini. “Moreover, we might explore in the future whether some of the tRNA changes during dengue infection could be druggable or targeted to potentially diminish the viral replication.”
Bazzini concluded, “From our discovery, we still need to better understand how the virus, the host cell or both might take advantage of this molecular mechanism to start investigating how we can use this molecular knowledge to actually prevent virus replication.”
Dr. Ariel Bazzini was speaking to Blake Forman, Senior Science Writer for Technology Networks.
About the interviewee:
Dr. Ariel Bazzini is an associate investigator at the Stowers Institute for Medical Research. Bazzini earned a PhD in biology from the National Institute of Agriculture Technology, Biotechnology Institute and University of Buenos Aires. His research focuses on gene regulation in development and disease and in unraveling the intricacies in RNA stability and translation.
Reference: Castellano LA, McNamara RJ, Pallarés HM, Gamarnik AV, Alvarez DE, Bazzini AA. Dengue virus preferentially uses human and mosquito non-optimal codons. Mol Syst Biol. 2024. doi: 10.1038/s44320-024-00052-7