Dengue is one of the world’s fastest-spreading mosquito-borne diseases, causing millions of infections annually. Half of the world’s population is now at risk, and transmission is increasing in many regions due to climate change1, 2. Researchers have long suspected that people who quietly clear dengue virus without ever developing symptoms may hold important clues to protection, but they remain difficult to examine directly. The new study published in Science Translational Medicine provides a uniquely detailed single-cell map of these cases.
A team from Mahidol University in Thailand, the Wellcome Sanger Institute in the UK, and international partners reports the first single-cell immune atlas of asymptomatic dengue, offering a rare look at how the immune system can defeat the virus without triggering illness. The work could help guide the design of safer and more effective dengue vaccines.
A rare opportunity in dengue research
Asymptomatic dengue is practically invisible to medical systems: people feel perfectly healthy, rarely seek care, and the window of detectable viruses in the blood is short. The new findings were made possible by a five-year household surveillance study that followed close contacts of confirmed dengue patients, building on community-based approaches first pioneered in Thailand through the EU-funded DENFREE project more than a decade ago.
“Over those five years, only eight true asymptomatic dengue infections were captured while the virus was still in the blood,” said Assoc. Prof. Ponpan Matangkasombut, an immunologist at Mahidol University. “These cases are incredibly rare and valuable, without them, we may not understand why some people clear dengue without any symptoms.”
These eight cases, along with others with mild and severe symptoms, became the foundation for a high-resolution immune map built from over 134,000 individual immune cells, profiled using single-cell RNA sequencing and immune receptor sequencing.
A tale of two immune responses
“The detailed cell-level data revealed sharp differences between immune responses in those who became sick and those who did not,” said Dr. Waradon Sungnak, an immunologist and computational biologist at Mahidol University. “Those without symptoms showed distinct patterns in key immune cell types, including CD8 T cells, natural killer cells, and antibody-producing cells such as those making IgA, which set them apart from symptomatic cases.”
“Symptomatic dengue, by contrast, displayed immune hallmarks associated with more harmful processes,” said Dr. Tiraput Poonpanichakul, also an immunologist and computational biologist at Mahidol University. “The features present in asymptomatic cases were largely absent in symptomatic dengue, which instead showed signs of antibody-mediated viral uptake and inflammation.”
Other biological signals helped distinguish asymptomatic cases from more severe diseases.
“We also observed cytokine-related signals that were more pronounced in symptomatic dengue, offering clues to why some infections escalate while others resolve,” said Dr. Natnicha Jiravejchakul, a former PhD student at Mahidol University, now a postdoctoral fellow at Osaka University in Japan.
The findings collectively paint a clearer picture of the push-and-pull between protective antiviral responses and inflammatory pathways that drive symptoms.
A powerful demonstration of single-cell technologies
Researchers say the work also showcases the value of single-cell approaches in infectious disease.
“This study shows the power of single-cell technologies to reveal immune states that would otherwise remain hidden,” said Prof. Sarah Teichmann, the former head of Cellular Genetics at Wellcome Sanger Institute and now a professor at the University of Cambridge. She is also one of the co-founders of the Human Cell Atlas initiative.
The dataset, publicly available to the research community, is expected to serve as a platform for future work in dengue and beyond.
“The dataset provides a valuable resource for the community and opens doors for further systems-level research in infectious and other diseases,” said Assoc. Prof. Varodom Charoensawan, a molecular and computational biologist at Mahidol University.
Toward better dengue vaccines
Current dengue vaccines may still face challenges, including potentially inconsistent protection across different virus serotypes. The new findings offer a roadmap for designing vaccines that mimic naturally protective responses rather than those associated with severe disease.
The authors note that future vaccines may benefit from boosting protective CD8 T cell responses while reducing inflammatory pathways linked to worse outcomes. The study represents a major step forward in understanding why dengue affects individuals so differently, and how the immune system can eliminate the virus without a hint of illness.
IMAGE CREDIT: NIAID
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