EXPERT ON DENGUE FEVER REPORTS BAD NEWS FROM THE FRONT

THE  By Dave Wilkins and John Woodford

The mosquito-borne dengue virus, which usually causes a severe flu-like illness called dengue fever, is infecting 50 million people annually, mostly children, and is a potential threat to 2.5 billion more--40% of Earth's population.

But despite advances in medical science in other areas, dengue fever (pronounced DEN-ghee, from Swahili ki-dinga) is likely to become an even worse scourge, according to Michigan researcher Rory M. Marks MD, an assistant professor of internal medicine at the U-M Medical School.

"Programs to control dengue infection have historically focused on killing the mosquito responsible for transmitting the virus to humans," Marks says. "These measures were very effective in the past but have failed in recent years. Basically, I think our war with the mosquito has been completely lost and is not going to get re-fought. We need to regroup, dodge the mosquito and take on the virus using new weapons provided by developments in molecular and cellular biology."

Thanks to Marks and other members of a U-M and University of Iowa research team, we now have new insights into the way the virus binds to human cells--and how to stop it from doing so.

The research team has discovered the mechanism the virus uses to attach itself to cells it will infect, and they can block it from doing so in laboratory tests. "It provides something to work from to develop a potential drug treatment and, perhaps, also a vaccine," Marks says.

In earlier studies, te researchers concluded that a particular dengue virus protein--called the "envelope protein"--is responsible for binding the virus to cells targeted for infection. Their latest work takes that a step further by showing that dengue infection occurs when the virus binds to a type of sugar molecule, heparan sulfate, found on the surface of the target cell.

Marks and his colleagues also prevented that binding from occurring--and inhibited the infection--through the use of a drug called Suramin, chosen because it mimics the structure of heparan sulfate. It's questionable whether Suramin ultimately will be used to treat dengue infections because of concerns about potential toxicity, Marks says, and as the research is refined other drugs may ultimately prove more effective. Theirs, however, was the first demonstration that a pharmaceutical can effectively prevent infection by dengue virus, and it has provided a basis for screening related compounds that may inhibit the virus safely and effectively.

A severe form of the disease--dengue hemorrhagic fever--attacks a half-million patients a year and kills 25,000, although basic medical care saves most victims. Symptoms include internal bleeding, circulatory failure, coma and shock.

Dengue virus is one of a large family of viruses, called flaviviruses, many of which cause serious human disease, including yellow fever and hepatitis C. Most flaviviruses have similar envelope proteins, and it is believed that they share the same basic mechanism for binding to cells. "We expect our work with dengue virus to also hold true for these other viruses," Marks says.

Marks says that "these gains in understanding about the pathogenesis of dengue virus infection occur on a background of continuing controversy about whether wealthy nations, particularly the United States, have a continuing responsibility for controlling diseases that mainly threaten developing countries." But any weakness of commitment to fighting dengue and other "tropical" disease is short-sighted, because dengue fever is making inroads in Puerto Rico and the continental United States.

Why is dengue penetrating the United States? Nobody is really sure. "Most of the cases are returning travelers who became infected in endemic areas," Marks says. "However, the major concern is with the small but growing number of cases of locally acquired infection in Texas. There had not been any locally acquired dengue within the continental United States for a decade when the first recent case was reported in 1995. There have now been approximately 30.

"This follows epidemics across the border in Mexico," he continues, "and it is thought to be due to the spread of infected mosquitoes over the border. A mosquito capable of carrying dengue virus is widely distributed through the US, and so there appears to be nothing to stop infected mosquitoes from spreading through the US."

After World War II, Marks says, "international programs based on widespread larvicidal spraying achieved remarkable reductions in the incidence of dengue virus infection."

"In the America's," he continued, "this program was managed and co-ordinated, on a hemispheric scale, by the Pan-American Health Organization. These were labor-intensive paramilitary programs aimed at killing mosquito larvae and eliminating sites of stagnant water accumulation close to human habitats that supported mosquito growth.

"The success of these programs led to complacency, and that, combined with a change in the political climate within the US, led to severe curtailment of funding and resulted in the control programs' being dismantled."

The resurgent mosquito is causing pandemic levels of dengue in parts of the tropical third world, with epidemic and endemic transmissions elsewhere in the tropics and sub-tropics, according to Marks.

Recent attempts to reintroduce mosquito control programs have failed for any and all of a bundle of reasons, Marks says. He cited the following:

¤  Lack of political support for an expensive long-term control program. "Programs work for a while, but when the incidence of infection drops, interest fades and the programs are canceled."

¤  Programs too limited in geography. "The mosquitoes do not respect national borders. A program in one country is defeated by the failure to control mosquitoes across a border."

¤  Health officials no longer have the same access to, and control over, human habitats that they previously enjoyed. "You only need to have one household within a densely populated area refuse access to control personnel for monitoring and spraying, to defeat the whole program."

¤  Governments' failing to accept responsibility for public health. "Puerto Rico is a good example. Dengue is causing increasingly frequent epidemics in Puerto Rico, yet the major funding for a local educational control program has been provided by Rotary International. This is to Rotary's credit, but is an indictment of the failure of government to accept responsibility for the public health."

What is expected to stop the virus from becoming a more significant public health risk is the generally more advanced level of human habitation in the US--that is, less stagnant water and less exposure to mosquitoes.

"I understand that the cases reported from Texas have mostly occurred in the context of poor living conditions," Marks says.

David Wilkins writes on health-related topics for the U-M Medical Center.