Research reveals clear infection strategies for Zika and dengue viruses

Zika and dengue viruses are very close relatives. Both are mosquito-borne flaviviruses, and both are specialized for infecting host dendritic cells.

But new Natural Communication Research led by scientists from the La Jolla Institute for Immunology (LJI) and UC San Diego shows that these two viruses are very different in how they make us sick.

Zika Virus uses stealth. Zika virus slips into dendritic cells, blocking nearby warnings T cells Dangerous. It's a classic horror movie cliche – Creeper is already at home and the phone line is disconnected.

Dengue viruses like shock and patience. Dengue viruses push dendritic cells to stir up molecules called proinflammatory cytokines, sending the immune system overdrive. As the body tackles this overwhelming immune response, the virus spreads to new host cells.

Understanding these different infection strategies is key to developing life-saving vaccines, says LJI professor Dr Sujang Shresta. Her team is working on developing a vaccine that utilizes virus-fighting T cells to combat Zika virus, dengue virus, and other flaviviruses with potential pandemics.

“Our ultimate goal is to develop vaccines against these extremely difficult viruses,” says Schresta, who led the collaboration with UC San Diego's Professor Aaron Carlin and Dr. Maryland. “Understanding how these viruses manipulate immune responses will help guide the development of the best vaccine approach.”

Why Zika-infected dendritic cells can't ask for help

This new collaboration is the first to show exactly how the Zika virus achieves sneak attacks. Using a technique pioneered by Carlin in postdoctoral studies in San Diego, California and LJI, researchers isolated only Zika or dengue infected dendritic cells from human blood samples. Gene expression was then examined in these cells to see how they responded to infection.

Zika-infected dendritic cells did little, but the researchers were able to see why in the end. They found that the Zika virus actively suppresses a key cell molecule called NF-κBP65. Without NF-κBP65, dendritic cells will be stuck in immature state and cannot promote T cells to combat infection.

In contrast, dengue viruses actually stimulate dendritic cells to produce large amounts of proinflammatory cytokines, and respond actively to the presence of the virus.

The findings help explain why many people develop weak immune responses to Zika and dengue viruses, says Ying-Ting Wang, Ph.D, a former LJI postdoctoral researcher and the first author of the current study. The new study also provides clues as to how Zika virus infects fetuses that develop past immune defenses in the placenta.

Zika virus inhibits all kinds of productive dendritic cell responses. I think it is the key to its pathogenesis and its ability to spread quietly and last within the infected human. ”

Aaron Carlin, Dr. Maryland, Professor San Diego, California

Currently, there are no effective vaccines or treatments against Zika and dengue viruses. New discoveries may help scientists to cover these viruses.

“Looking at these human cell cultures helps people understand what's going on,” says Schresta. “Our findings inform us how vaccines and antiviral agents develop that manipulate these cellular pathways.”

Why Zika and Dengue Vaccines Are Important

Schresta and Carlin want to continue their research into flaviviruses. They know they don't have time to lose.

Many mosquito-borne viruses are spreading rapidly as a means of transporting diseases Rats Mosquitoes expand into new habitats. In fact, last year was the worst record of reported dengue virus cases. According to the World Health Organization (WHO), the dengue virus infected between 100 million and 400 million people in 2024. These cases included the first case of locally transmitted dengue virus infection in San Diego County.

Many flaviviruses also have the potential to be a pandemic. In a 2024 report listing Zika virus, dengue virus, West Nile virus, tick-borne encephalitis virus, and the top pathogen yellow fever virus for “prioritization” in preparation for the upcoming pandemic.

Schresta has been monitoring the spread of these viruses in recent years. As she explains, many of these viruses overlap in the same region. As a result, millions of people are at risk of infection from a variety of flaviviruses attacking dendritic cells from different angles.

Shresta is making a leading effort at LJI to develop a “pamflavivirus” vaccine that could fight many flaviviruses at once. “Our challenge is to develop a safe and effective vaccine against not just one virus, but all these closely related flaviviruses,” says Schresta.

At the same time, Carlin is considering developing antiviral agents that could interfere with Zika's ability to suppress NF-κBP65. He also wants to investigate exactly how dengue viruses overstimulate the immune system.

“Understanding how dengue virus stimulates people's shock-like phenotypes allows for precision-inducing therapy that prevents death and hospitalization without hampering the immune system's ability to clear the virus,” says Carlin.