Researchers link genetic ancestry to severity of dengue fever

For the first time, the extreme variability in dengue fever has been linked to a biological mechanism, potentially opening doors to new treatments and vaccines for the most common mosquito-borne disease worldwide. The study was published today in Proceedings of the National Academy of Sciences (PNAS) by researchers from the University of Pittsburgh, UPMC and Instituto Aggeu Magalhães in Brazil.

Cases of dengue fever, commonly known as "breakbone fever" for the excruciating joint pain that is the hallmark of the disease, have been rising around the world in recent years. More than half the global population is at risk.

There's an urgent need for better prevention and treatment for this global threat. Dengue outbreaks can quickly overwhelm local hospitals."

Priscila Castanha, Ph.D., MPH, lead author, assistant professor of infectious diseases and microbiology at Pitt's School of Public Health

The course of the disease varies widely from person to person. Some are asymptomatic; 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, Ph.D., 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-like Brazil, Colombia, Haiti and Cuba-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.

In this 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. The participants consented to contributing their tissues to this study.

"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 genetic markers known as single nucleotide polymorphisms. The team then injected each sample with dengue virus, observed the samples' subsequent immune responses over a 24-hour period and compared them.

The team found that the inflammatory response 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.

The team further 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. 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. In future studies, they 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. Evolution has made its mark on everyone's DNA," said Castanha.

Other authors on the study are Michelle M. Martí, M.S., Parichat Duangkhae, Ph.D., Jocelyn M. Taddonio, M.S., Kristine L. Cooper, M.S., Megan Wallace, M.S., Gwenddolen Kettenburg, M.S., Geza Erdos, Ph.D., Hasitha Chavva, M.S., Aleena Alex, M.S., Pharm. D., J. Peter Rubin, M.D., Simon C. Watkins, Ph.D., Louis D. Falo, Jr., M.D., Ph.D., and Jeremy J. Martinson, Ph.D., all of Pitt; and Ernesto T. A. Marquesa, M.D., Ph.D., of Pitt and Instituto Aggeu Magalhães.

This research was supported by Pitt, the Institute for Precision Medicine, the Richard K Mellon Foundation for Pediatric Research and the National Cancer Institute (P30CA047904).