Lethal Emergence: Tracing the rise of dengue fever in the Americas

A spate of deadly outbreaks of dengue fever in Latin America in recent years stems from the 1994 arrival of a potent version of the disease that is endemic to India, genetic analyses of viruses reveal. That viral incursion followed the 1981 arrival of another lethal dengue strain in Cuba, apparently from Africa. These two variants have together changed dengue fever in the New World from at most a painful ailment into a potential killer.

DENGUE DIFFUSION. Since its introduction in 1994, the potent dengue 3 subtype III virus has spread steadily throughout Latin America. Mosquitoes transmit dengue fever. Adapted from Messer/Emerging Infectious Diseases

DENGUE DIFFUSION. Since its introduction in 1994, the potent dengue 3 subtype III virus has spread steadily throughout Latin America. Mosquitoes transmit dengue fever.
Adapted from Messer/Emerging Infectious Diseases

The mosquito-borne dengue virus comes in four distinct types, designated dengue 1, 2, 3, and 4. Fatal cases of dengue anywhere in the world typically hit people who’ve been previously infected by a dengue type different from the one that causes the final illness. This pattern, an oddity among viral diseases, has slowed the development of a vaccine. In a separate study, Thai and British researchers shed light on this failure of the immune system.

Usually, each dengue type causes mild disease but sometimes brings on high fever, severe headaches, vomiting, listlessness, and joint pain. Even so, dengue fever is seldom fatal.

However, in the form called dengue hemorrhagic fever, an infection can cause shock, internal bleeding, and death. Ecologist William B. Messer of the University of North Carolina at Chapel Hill and his colleagues report in the July Emerging Infectious Diseases that recent outbreaks of this hemorrhagic fever in Latin America, where lethal dengue had been rare, are attributable to the 1994 influx of the India-derived virus, dubbed dengue 3 subtype III.

By poring over the genetic makeup of virus particles obtained worldwide from patients with dengue hemorrhagic fever, the researchers found that dengue 3 subtype III exactly matches viruses gleaned from outbreaks in Mozambique in 1985 and Sri Lanka in 1989. Those viruses have genetic roots in an Indian dengue virus, which probably first arrived in Panama or Nicaragua before spreading in the Americas, Messer says.

Earlier in that decade, a variant of dengue 2 had arrived in Cuba and spread from there. “It was a double whammy,” Messer says. “Now, there are two [severe forms of the virus] floating around, causing hemorrhagic dengue.”

By using genetics to track dengue, scientists may learn the virus’ patterns of movement and, ideally, how to predict outbreaks, Messer says. The World Health Organization estimates there are 20 million cases of dengue infection worldwide every year.

Meanwhile, other scientists who are analyzing blood samples from Thai children with severe dengue are investigating how this hemorrhagic fever incapacitates people.

Each of the four types of dengue virus induces specific immunity, so a person can get sick from dengue four times in a lifetime. However, a second infection is often worse than the first. Earlier research on severe cases showed that antibodies made during a second infection don’t neutralize the virus.

Making matters worse, the immune system’s other defense strategy also can fail. T cells that mobilize during a second dengue infection often don’t target the new virus, instead directing their immune attack toward the viral type encountered previously, says Gavin Screaton, an immunologist at John Radcliffe Hospital in Oxford, England. That leaves an individual laden with the second virus, Screaton and his colleagues report in the July Nature Medicine.

Dengue infections marked by high viral loads correlate with excessive bleeding in the patient, notes Francis A. Ennis of the University of Massachusetts Medical School in Worcester. Aggressive T cell responses may be part of the problem, some studies suggest. “They make [proteins] that cause capillaries to leak,” Ennis says.

A critical step toward making a dengue vaccine is to understand the human response to the virus, Screaton says. Any vaccine for dengue must address all four types of the virus at once or risk leaving individuals vulnerable.


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