![A skin section from an individual with European ancestry showing infected skin cells (with blue nuclei) and macrophages (magenta) around the epidermal-dermal junction (white dotted line) 24 hours after exposure to dengue virus (green). [Priscila Da Silva Castanha]](https://www.genengnews.com/wp-content/uploads/2025/06/low-res-16.jpeg)
A skin section from an individual with European ancestry showing infected skin cells (with blue nuclei) and macrophages (magenta) around the epidermal-dermal junction (white dotted line) 24 hours after exposure to dengue virus (green). [Priscila Da Silva Castanha]
Researchers at the University of Pittsburgh, University of Pittsburgh Medical Center, and Instituto Aggeu Magalhães, have for the first time linked the extreme variability in severity of the mosquito-borne viral disease, dengue, between individuals, to the influence of genetic ancestry on inflammatory responses in the skin.
The team exposed human skin explants from donors of European or African ancestry to dengue virus (DENV) and examined immune responses. Their findings indicated that inflammatory responses in the skin that promote virus replication and spread are influenced by genetic background, with immune activity increasing with greater European ancestry. The researchers suggest the findings may help to explain why African ancestry is associated with a lower risk of severe dengue, and could point to new approaches to treatments and vaccines for dengue, which is the most common mosquito-borne disease worldwide.
Lead author Priscila Castanha, PhD, MPH, assistant professor of infectious diseases and microbiology at Pitt’s School of Public Health, and colleagues reported on their findings in PNAS, in a paper titled “Genetic ancestry shapes dengue virus infection in human skin explants.” The team concluded in their report, “Our findings show that the early innate immune response of human skin to DENV infection is strongly influenced by genetic ancestry…Genetic ancestry should be considered when predicting a patient’s likelihood of severe dengue, and when assessing efficacy and adverse events associated with dengue vaccines.”
Cases of dengue fever, commonly known as “breakbone fever” for the excruciating joint pain that is the hallmark of the disease, is the most prevalent arthropod-borne viral disease in humans, affecting tens of millions of people, the authors noted. Cases have been rising around the world in recent years, and more than half the global population is at risk.
“There’s an urgent need for better prevention and treatment for this global threat,” said Castanha. “Dengue outbreaks can quickly overwhelm local hospitals.”
The course of the disease varies widely from person to person. Some are asymptomatic while others experience dengue’s painful flu-like symptoms and then recover within days or weeks. “But 5% have serious bleeding, shock and organ failure—they can be critically ill within two days,” said senior author Simon Barratt-Boyes, PhD, professor of infectious diseases and microbiology at Pitt Public Health and immunology at Pitt School of Medicine.
For decades, epidemiologic studies have documented a puzzling phenomenon. In countries with ethnically diverse populations, people of African ancestry tend to have milder cases of dengue, while people of European ancestry have more severe disease. But no one could explain why. “Beginning more than four decades ago, multiple reports from South and Central American countries with genetically admixed populations described the protective effects of African ancestry from severe dengue,” the authors stated. “African ancestry is associated with protection against severe dengue, but the mechanisms are unknown.”
For their newly reported study the team used a model they developed with samples of human skin that had been donated by individuals who had undergone elective skin-reduction surgeries after profound weight loss.
“We used skin because it is an immunologic organ and the body’s first line of defense against dengue infection,” said Barratt-Boyes. When maintained in culture under proper conditions, the tissue samples used in this model can survive and carry out their normal immune functions for days, providing a unique opportunity for scientific study, he added, “because the skin is where the story begins with all mosquito-borne diseases.”
The study focused on samples from individuals who had self-identified as having European or African ancestry. First, the researchers objectively measured the ancestral geographic origins written into the skin samples’ DNA by analyzing single nucleotide polymorphism genetic markers. The team then injected each skin sample with dengue virus and observed and compared the samples’ subsequent immune responses over a 24-hour period.
The team found that the inflammatory response to the virus was much greater in skin from people with higher proportions of European ancestry. And unfortunately, in severe dengue, this immune response is prone to “friendly fire.” The virus infects inflammatory cells, actually recruiting them to spread the infection instead of fighting it off. This dynamic is believed to be what is so damaging to blood vessels and organs in severe cases of dengue fever.
In the samples from donors of European ancestry, the team saw this friendly fire in action as myeloid cells mobilized to confront the virus, then themselves became infected. The turncoat cells then moved out of the skin and spread out into the dish—similar to how they would spread within the body, traveling through the bloodstream and into lymph nodes. “We show using isolated human skin specimens that dengue infection elicits a marked inflammatory response in European ancestry skin, leading to infection of resident cells that then migrate out of skin, spreading infection,” the team wrote in summary. “In contrast, African ancestry skin has significantly less inflammation in response to infection, limiting replication and spread.” The protective effects of African ancestry from severe dengue begin at the initial stages of infection, the scientists also note.
The team showed that the problem was not the skin itself—it was indeed the inflammatory response. In the samples from individuals with higher proportions of African ancestry, the researchers added inflammatory molecules called cytokines, and the friendly fire ensued. “Infiltration and infection of macrophages in African ancestry skin increased to that of European skin after blocking IFN-α and providing interleukin-1β.” Then, when the team blocked the inflammation within those same samples, the virus’s rate of infection in the cells plummeted.
“It makes sense that, in parts of the world where ancient populations were exposed to deadly mosquito-borne viruses—like the one that causes yellow fever, which is related to dengue viruses and has been around for a very long time—those with a limited inflammatory response had an advantage,” said Barratt-Boyes. “They then passed that advantage down to their descendants.” Ancient Europeans’ descendants, however, lack that ancestral exposure and the evolutionary adaptation it made possible.
The authors hope that, eventually, the mechanism they’ve identified could be exploited for precision medicine approaches to things like risk assessment, triage in an outbreak, therapies and vaccines. “Genetic ancestry may affect the way different populations respond to dengue vaccines, which are weakened viruses given in skin,” they pointed out. In future studies, the investigators hope to describe this mechanism in further detail, including which specific gene variants contribute to protection from severe dengue. The current study’s broader analysis of geographic ancestry could be an important first step to that end.
“Ancestry does affect biology,” said Castanha. “Evolution has made its mark on everyone’s DNA.”
