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The Devil's Disease: Dengue Fever

Dung Hoang

The Devil's Disease: Dengue Fever (continued)

Dengue’s spread is only part of the story. For dengue fever is not just a virus, it is four viruses. And in a given year, a region may experience an outbreak of one or two of those virus serotypes, and sometimes all four at the same time.

The challenge of a virus, according to George Dimopoulos, PhD, an MMI associate professor, “is its ability to rapidly mutate, making it difficult for the human immune system to resist it.”

With most viruses, a survivor is usually immune to subsequent infections because of antibodies that alert the body to resist new viral invasions. Vaccines—usually weakened forms of a virus—build similar antibodies for resistance. With the eradication of smallpox and near-eradication of polio, vaccine-fostered immunity is a sacred given in public health.

But dengue fever commits sacrilege and it even has its own name: antibody-dependent enhancement. “There’s one thing we are fairly certain of,” says Durbin. “If you have an antibody to a serotype, say Dengue 1, and you are infected with Dengue 2 virus, your Dengue 1 antibody won’t protect you.”

That’s because, says Durbin, the antibody binds itself to the new dengue strain, in effect joining forces with the new virus and helping it gain entry into target cells where it can then replicate. As a result, the bloodstream now contains higher levels of the virus than during the first infection. Often this triggers dengue hemorrhagic fever. Any of the four dengue serotypes can combine with the antibody from any other serotype to cause DHF.

It is, according to Halstead, “a most amazing perversion of the immune response.”

“The cells that are supposed to scout out and kill viruses and the antibodies that are supposed to destroy viruses form an unholy complex to defeat our immune system and promote the life of the dengue virus,” he told a New York Academy of Sciences gathering last year.

The ramifications for dengue fever vaccine development are daunting: A dengue vaccine must be able to combat all four serotypes at the same time. But the hazards only begin there.

“In the vaccine world, two big questions overhang our studies,” says Durbin. “One is close to being answered: If we introduce a live vaccine into people who have a pre-existing antibody, can that vaccine cause severe disease?”

Because a vaccine will essentially be a weakened form of the disease, she says, most researchers believe it’s not likely to occur.

“The greater concern,” she adds, “is what happens if the vaccine we introduce doesn’t produce a balanced immune response in individuals and, over time, their antibodies to various serotypes decline at different levels? And supposing an individual never did develop a good response to one of the serotypes. Are we going to put people at risk for more severe disease months or years down the road? Nobody knows the answer. The only thing that will answer it is long-term surveillance studies of vaccinated populations.”

There are other troubling questions. “We think a vaccine will reduce transmission of dengue or reduce the circulation of dengue in endemic areas,” she says. “But what happens if it reduces the transmissibility below the level that will sustain dengue in a given community? If people aren’t being exposed, will their immunity drop and make them more susceptible should somebody come into their region and reintroduce dengue? We just don’t know. We won’t until we follow them over years and see if they are able to maintain antibody levels or not.”

Most dengue research comes on what scientists refer to as “the human side” of the disease. Far fewer researchers attempt to solve the dengue riddle by understanding the biology of Aedes aegypti, the territory held by those on “the mosquito side.”

George Dimopoulos has built an international reputation as an authority on mosquitoes that carry pathogens for malaria and dengue. In 2001, he started the Dimopoulos Group, a research lab at the Imperial College of London. In 2003, his group became part of the Johns Hopkins Malaria Research Institute in the School’s MMI Department.

“I truly believe,” he says, “that we will never be able to design an efficient strategy to eliminate dengue and other mosquito-borne diseases if we don’t understand the biology of the pathogen and how it interacts with the human and the mosquito.”

Dimopoulos carries out his research in CDC-approved, Biosafety level 2 and 3 facilities housing tens of thousands of mosquitoes. Collected during field trips to tropical regions, some of the mosquitoes are Anopheles gambiae that can carry Plasmodium, the malaria-causing parasite; others are Aedes aegypti. Most are harmless, not yet infected with a pathogen.

Those that have been infected—in one of four brightly lit, white-on-white contaminant labs—are kept in carefully screened cages in small closets off the labs. Temperature and humidity level have been adjusted to tropical conditions. Here the mosquitoes lay eggs in special trays and are fed on human or mouse blood.

To an untrained eye, the Anopheles and Aedes mosquitoes look the same. But, it’s what’s inside of them that intrigues Dimopoulos. He notes that the Plasmodium parasite that causes malaria cannot infect the Aedes mosquito nor can the dengue virus infect the Anopheles.

“It’s not known why that is,” says Dimopoulos. “A pathogen may, for example, require certain receptors in the mosquito’s gut—factors that are present in one species but not in the other—to establish infection.”

A virus cannot propagate independently of its host. The malaria parasite, with its 6,000 genes, replicates its DNA on its own while dengue, with only 10 genes, has to use the machinery of the host cell to propagate.

Unlike the malaria parasite, once the dengue virus has taken hold in the mosquito’s cells, says Dimopoulos, the way it interacts parallels the way it behaves in a human cell. “It’s probably utilizing very similar cellular machinery in [both] its hosts,” he says. “That is why research we do on dengue in the mosquito may also be used to understand how dengue infects humans. The actions are quite similar.”

In a manner very close to the way the human immune system tries to fight off an invasion by a dengue virus, the Aedes aegypti flexes its own defenses against viral pathogens. Researchers know of three immune-related cellular pathways in the Aedes mosquito. In previous work, Dimopoulos’s group has shown that two of them—the Toll and JAK-STAT pathways—defend against the dengue virus. “These defense systems do not seem to be sufficient in the Aedes mosquito,” says Dimopoulos. If they were, the mosquito could fight off the infection. “But these pathways are doing something.”

It’s even probable, that this anti-dengue response may be sufficient against dengue in different mosquito strains and species, explaining why they can’t be infected by the virus. “But we have just started to understand these defenses and their pathways and we don’t really understand the resistance mechanisms yet.”

Historically, notes Dimopoulos, wherever dengue and malaria have been controlled it has been through the mosquito—either through avoidance strategies or with insecticides. But he believes that if there were a way to manipulate some of the factors in the cells of the mosquito’s gut—those that allow these pathogens to propagate, or those that act against the pathogens—the virus and the parasites could not survive. 

“So we are pursuing a different strategy,” he says. “Our idea is to cure the mosquito—by making it resistant to the pathogens.”

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  • Ifelayo

    Hyattsville, MD 07/09/2010 08:51:20 AM

    I like this display of a combination of efforts to fight an old scourge! With patient persistence following these tracks, we should overcome Dengue and hopefully Malaria too...

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