Researchers at the Stowers Institute have discovered the ingenious methods employed by the dengue virus to replicate within host cells. This groundbreaking study could pave the way for novel antiviral treatments and vaccines.
With mosquito-borne viral infections spreading far beyond tropical regions, global health faces a daunting challenge. Dengue virus, in particular, has become a major concern, infecting up to 400 million people each year worldwide, according to the World Health Organization. Despite its prevalence, there are currently no available treatments for this debilitating disease. However, groundbreaking research led by the Stowers Institute for Medical Research promises to change the landscape of antiviral treatment and vaccine development.
In a pioneering study published in Molecular Systems Biology, researchers led by Luciana Castellano, a predoctoral researcher at Stowers Institute, under the supervision of Associate Investigator Ariel Bazzini, have uncovered surprising tactics used by dengue virus to propagate within host cells.
The team discovered that the dengue virus genome utilizes less efficient codons — or genetic “vocabulary” — to synthesize its proteins. A codon is a sequence of three nucleotides in RNA that acts like a “word” in the genetic code to produce proteins. Intriguingly, the study found that the dengue virus prefers to use codons that are less optimal in mosquito and human hosts, contrary to the researchers’ initial hypothesis.
“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,” Bazzini said in a news release.
“During infection, host cells and viral invaders are at war,” Castellano added. “Like building weapons, both viruses and cells need to build proteins to fight and defend themselves.”
This revelation not only sheds light on the protein production strategies of dengue but also suggests a broader principle affecting many viruses, including HIV and SARS-CoV-2. The research found that a substantial number of viruses use less efficient codons as a strategic advantage, exploiting host cell resources in a way that benefits the virus.
The concept of codon optimality — whether a particular codon is efficient or optimal in one species but not in another — plays a significant role in this process. The Bazzini Lab has been investigating how codon optimality affects protein production and RNA stability in humans and other vertebrates. This study marks the first time that similar principles have been identified within the mosquito genome.
“We were surprised to find that mutations in the dengue virus genome toward these less efficient codons increased dengue virus fitness in both mosquito and human cells,” the study’s co-author, Ryan McNamara, a bioinformatics analyst in the Bazzini Lab, said in the news release.
This strategic use of less efficient codons by viruses could also influence how host-pathogen relationships evolve over time, potentially altering the way we understand viral evolution and host defenses.
“Fundamentally, this work has altered how we think about the relationship between a virus and a host cell,” Bazzini added. “In the future, we hope to better understand the mechanism by which viruses are benefitting from using these inefficient codons, and which molecules viruses may be manipulating to gain control.”
Given the rapid spread of mosquito-borne viruses like dengue, particularly with reports from the Centers for Disease Control and Prevention (CDC) indicating that cases in the Americas have doubled since last year, this research comes at a crucial time.
“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,” Bazzini warned.
The study not only marks a significant step forward in understanding viral replication but also opens new avenues for developing antiviral treatments and vaccines. This collaborative effort also involved contributions from Horacio Pallarés from the Stowers Institute, Andrea Gamarnik from Fundación Instituto Leloir-CONICET, Argentina, and Diego Alvarez from Universidad Nacional de San Martín-CONICET, Argentina.