Mosquito-borne viral diseases, previously restricted to tropical areas, are increasingly emerging in other regions. According to the World Health Organization, the dengue virus affects around 400 million individuals around the globe each year, and currently, there are no known treatments for this disease. Recent research has revealed unexpected methods by which dengue and many other viruses reproduce within their hosts, which could lead to the creation of new antiviral treatments and vaccines.
Mosquito-borne viral diseases that were once limited to tropical climates are now on the rise. The dengue virus infects roughly 400 million people globally each year, as estimated by the World Health Organization, and no treatments are currently available to combat this illness. Research from the Stowers Institute for Medical Research has recently exposed surprising mechanisms that dengue and various other viruses utilize to replicate in their hosts, offering potential pathways towards the development of innovative antiviral therapies and vaccines.
Led by Stowers Predoctoral Researcher Luciana Castellano in the lab of Associate Investigator Ariel Bazzini, Ph.D., the findings, which were published in Molecular Systems Biology on July 22, 2024, indicate that the dengue virus genome utilizes less effective codons, or “vocabulary,” to produce its proteins by hijacking the host’s cellular machinery for replication and dissemination. A codon is a group of three nucleotides, serving as “words” in genetic language that assist in protein formation. The research revealed that hundreds of other viruses also employ less efficient “words” within their genetic code while infecting both mosquito and human hosts.
“Now that we’ve identified the codon usage of dengue and other viruses during cell infection, we have valuable insights for potentially preventing these serious diseases,” stated Bazzini.
“In the battle between host cells and viral invaders, both sides require proteins to launch their defenses,” added Castellano. “It’s a constant struggle.”
To spread, the dengue virus requires the proteins encoded within its single-stranded RNA genome, but it can’t produce these proteins independently. Therefore, the virus relies on the host cell’s protein synthesis machinery, leading researchers to suspect that it would preferentially use codons or “language” akin to those of humans and mosquitos.
“The genetic code is universal across all living organisms, comprising 64 codons—three-nucleotide sequences that define the amino acids forming proteins,” Bazzini explained.
The nature of the genetic code allows several codons to correspond to the same amino acid. Codons serving this purpose are known as synonymous codons and act like synonyms in language.
However, just as synonyms can possess distinct meanings, each synonymous codon has unique characteristics that can influence how efficiently a cell can produce proteins and the stability of RNA. Moreover, a specific synonymous codon can work well in one species but might not be effective in another, a concept referred to as codon optimality. The Bazzini Lab investigates codon optimality in humans and other vertebrates, and this study marks the first time researchers have identified a unique optimality code in the mosquito genome.
The researchers discovered that the dengue virus tends to utilize synonymous codons considered less optimal for both mosquitos and humans, contrary to their initial expectations.
“We were taken aback to find that the dengue virus relies more on less efficient codons of its host, likely as a tactic to avoid the host’s antiviral responses,” Castellano remarked.
“As viruses infect their hosts, they undergo mutations. Surprisingly, our research found that mutations in the dengue virus genome that shift towards these less efficient codons actually enhance the virus’s ability to thrive in both mosquito and human cells,” explained Ryan McNamara, a Bioinformatics Analyst in the Bazzini Lab whose insights were crucial to this research.
The team also analyzed a variety of other human-infecting viruses and discovered that many of them, such as HIV and SARS-CoV-2, also prefer less efficient codons in relation to humans. This suggests that these viruses have adapted to use an “inefficient” genetic makeup to exploit host cellular resources in ways beneficial to their survival. This shared preference among viruses offers insights into their evolutionary paths and how the relationships between hosts and pathogens evolve over time.
“Essentially, this research changes our perspective on the interaction between viruses and host cells,” Bazzini noted.
“Going forward, we aim to better understand the mechanisms through which viruses benefit from using these inefficient codons, as well as the molecules they might manipulate to gain dominance,” Castellano added.
The Centers for Disease Control and Prevention reported that dengue cases have doubled in the Americas just since last year, highlighting an increased risk of infection in the U.S.
“As mosquitos are migrating to wider global areas, we need to consider seriously how to fight back against dengue and other mosquito-borne viral infections,” warned Bazzini.