University of Vermont and Upstate Medical University researchers show dengue replicates inside memory B cells — and identify signaling pathways that existing drugs might one day target.
Dengue fever has a cruel twist that has puzzled scientists for decades. Surviving one infection does not necessarily make the next one easier. In fact, a second infection with a different strain of the virus can be far more dangerous than the first. A new study suggests part of the reason may lie in a surprising place: the very immune cells that are supposed to remember the virus and help defeat it.
Researchers at the University of Vermont’s Robert Larner, M.D. College of Medicine and Upstate Medical University in Syracuse, New York, have found that dengue virus can infect and replicate inside memory B cells, a type of immune cell long thought of as purely protective. The findings, published in the Journal of Virology, also identify molecular pathways the virus depends on to get in, pointing toward potential new treatments.
“This work challenges existing assumptions about how dengue interacts with the immune system,” said Sean Diehl, a professor of Microbiology and Molecular Genetics at UVM.
A global and growing threat
Dengue is spread by mosquitoes and comes in four distinct types, known as DENV1 through DENV4. It threatens roughly 40 percent of the world’s population, including parts of the southern United States. About 100 million people are infected each year, and more than 4 billion people live in areas where dengue-carrying mosquitoes are present. Severe cases can cause life-threatening damage to blood vessels and dangerously low blood pressure.
Despite that burden, there are no approved drugs that specifically target the dengue virus. Vaccines exist, but they have faced challenges with broad implementation and effectiveness, in part because of the very complexity that makes repeat infections so treacherous.
When antibodies help the enemy
Scientists have long understood one mechanism behind severe repeat infections, known as antibody-dependent enhancement. After a first infection, the body produces antibodies against that particular dengue type. If a person later encounters a different type, those antibodies may bind to the new virus without neutralizing it — and instead help it slip into certain immune cells, where it can multiply.
The Diehl lab and the lab of Adam Waickman, an associate professor of Microbiology and Immunology at Upstate, previously identified a related phenomenon involving B cells, which they named B cell receptor-dependent enhancement. In this case, the virus gains entry to B cells through the B cell receptor, the molecular antenna the cell normally uses to recognize its target.
A reservoir that lasts for years
The new study zeroed in on memory B cells, the long-lived cells that “remember” a pathogen after infection and stand ready to mount a faster response the next time. The team tested dengue-specific memory B cells and found that they could be infected by all four dengue types. Once infected, the cells produced infectious virus.
That combination is significant. Memory B cells persist for years after an initial infection, precisely so they can respond quickly to a repeat encounter. But the new findings suggest that same longevity could make them prime targets when a person is later exposed to a different dengue strain — cells primed to recognize dengue becoming, in effect, doorways for it.
The researchers used advanced microscopy to visualize how the virus enters these cells, building a detailed picture of the process.
Finding the weak points
Beyond showing that infection happens, the team identified molecular signaling pathways activated by the B cell receptor that the virus needs in order to infect the cells. Blocking those pathways could, in principle, shut the door.
That opens an intriguing possibility. Several drugs that target B cells or their signaling are already approved for treating cancers and autoimmune diseases. The researchers suggest that similar approaches might be adapted to dengue, potentially giving clinicians a head start on developing treatments rather than starting from scratch. Future strategies might even aim to selectively eliminate or modify high-risk memory B cells after a first infection, reducing the danger of a severe second one.
Those ideas remain speculative for now. The study was conducted in the laboratory, and translating it into therapies would require extensive further work to establish safety and effectiveness — particularly since memory B cells also play an essential role in protecting against many other infections.
A team effort
Diehl credited the early-career researchers who carried out the work. “It is a high bar to show something genuinely new in dengue research,” he said. “I am very proud of this high-quality data produced by our trainees who rose to the occasion.”
The study was co-led by Gaby Madrigal, a graduate student in UVM’s Cellular, Molecular, and Biomedical Science program, and Chad Gebo, a staff scientist and recent PhD graduate at Upstate. Menelaos Symeonides, an assistant professor of Microbiology and Molecular Genetics at UVM, also contributed.
As dengue spreads into new regions with the expanding range of its mosquito carriers, understanding exactly how the virus exploits the immune system has taken on new urgency. The discovery that it can commandeer the body’s long-term defenders adds an unexpected chapter to that story — and, perhaps, a new place to fight back.
The research was funded by the National Institute of Allergy and Infectious Diseases and the National Institute of General Medical Sciences.
Featured image: Aedes mosquito and dengue virus particles. Credit: NIAID
Notes
- Madrigal, G., et al. “Molecular and biophysical requirements for B cell receptor-dependent enhancement of dengue virus infection.” Journal of Virology, July 20, 2026. DOI: 10.1128/jvi.02216-25.
- University of Vermont. “Study reveals dengue virus can infect immune cells meant to fight disease.” News release via EurekAlert!, July 27, 2026. https://www.eurekalert.org/news-releases/1137755
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