July 31, 1997 ANN ARBOR---Researchers have a new understanding of the way dengue virus binds to human cells---and how to stop it from doing so.
The mosquito-borne dengue virus causes dengue fever, a severe flu-like illness which the World Health Organization (WHO) calls "the most important and rapidly increasing arbovirus in the world."
The disease is prevalent in Third World tropical regions and spreading to sub-tropical developed countries, including the United States. WHO estimates that 50 million cases of dengue (pronounced DEN-ghee) fever occur worldwide each year, including a potentially deadly form of the disease called dengue hemorrhagic fever.
Most cases occur in children.
A team of researchers from the University of Michigan and the University of Iowa have gained new insights into the way the virus attacks at a cellular level. Their findings will be published in the August issue of Nature Medicine.
"Dengue is a very significant world public health problem which has largely been ignored in the developed world," said Rory Marks, M.D., a member of the research team and an assistant professor of internal medicine at the U-M. "There's no specific treatment for infection and no way to prevent progression to the more deadly forms of the disease. No vaccine is available or likely to become available anytime soon.
"Programs to control dengue infection have focused on killing the mosquito responsible for transmitting the virus to humans," Marks said. "These measures were very effective in the past but appear to have failed in recent years. The mosquitoes appear to be winning this latest war."
New approaches for the control of dengue virus infection---specifically aimed at aspects of dengue virus infectivity other than mosquito control---are urgently needed, Marks said.
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 treatment," Marks said.
Marks points out that dengue fever is:
--An enormous social and economic burden throughout much of the developing world.
--Spreading to the developed world, including frequent epidemics within U.S. territory, in Puerto Rico.
--Increasingly prevalent after the withdrawal of mosquito control programs. "It is controversial whether wealthy nations, particularly the United States, have a continuing responsibility for controlling diseases that mainly threaten developing countries," Marks said.
In earlier studies, the 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 they identified as heparan sulfate, which is 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, Marks said. This, however, is the first demonstration that a pharmaceutical can effectively prevent infection by dengue virus, and it provides a basis for screening related compounds which may inhibit the virus safely and effectively.
Dengue virus is one of a large family of viruses, called flaviviruses, many of which cause serious human diseases. These include yellow fever and hepatitis C viruses. Most flaviviruses have similar envelope proteins, and it is expected 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 said.
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Background on dengue fever from the World Health Organization
--Dengue fever is a severe flu-like illness spread by mosquitoes. It's symptoms include fever, intense headache and eye pain, rash, diarrhea, and pain in the muscles and joints. There is no cure, but recovery typically is complete within 10 days. It is estimated that dengue fever afflicts 50 million people---mostly children---each year.
--Dengue hemorrhagic fever (DHF) is a potentially deadly form of the infection. It can cause internal bleeding, circulatory failure, coma, and shock. An estimated half-million patients require hospitalization for DHF each year, of which 25,000 die. There is no cure, but basic medical care saves most patients.
--The prevalence of dengue virus infection has increased dramatically in recent years. It is endemic in more than 100 countries in Africa, the Americas, the eastern Mediterranean, southeast Asia, and the western Pacific. Prior to 1970 , only nine countries had experienced epidemics of dengue hemorrhagic fever. By 1995, that number had grown to at least 41.
--Two-and-a-half billion people---40 percent of the Earth's population---are at risk of dengue infection.
--In 1996, the WHO called the resurgence of infectious diseases, including dengue infection, a global crisis that is crippling the socio-economic development of many Third World countries.
--In 1995, the worst dengue epidemic in Latin America and the Caribbean in more than a decade struck at least 14 countries, causing more than 200,000 dengue fever cases and almost 6,000 cases of dengue hemorrhagic fever.
--That same year, health officials confirmed the first case of dengue fever contracted from within the continental United States in a decade---in Hidalgo, Texas, with 30 additional cases later found in the same region.
Sources of additional information
Centers for Disease Control, Dengue Branch, Division of Vector-Borne Infectious Diseases, National Center for Infectious Diseases, San Juan, Puerto Rico; 809-766-5181. The CDC also operates the following dengue home pages: http://www.cdc.gov/incdod/EID/vol1no2/gubler.htm http://www.cdc.gov/incdod/publications/brochures/deng_q&a.htm
World Health Organization, Division of Control of Tropical Diseases, Geneva, Switzerland; 4122-791-3221. WHO's dengue home page is at http://www.who.ch/programmes/ctd/diseases/deng/dengmain.htm
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