July 4, 2000 New Drugs and Vaccines on the Horizon
For the first time, scientists have found a way to turn a fruit fly into a surrogate mosquito, able to carry malaria and infect chickens with the deadly disease. Their approach, reported in the June 30 issue of Science, may pave the way for better anti-malarial, transmission-blocking vaccines, and engineered mosquitoes that are resistant to malaria.
Malaria remains one of the most devastating public health menaces in the world today, killing more than 1 million people a year. Nevertheless, scientists know very little about how mosquitoes carry the disease and transmit it from person to person, largely because the insects are difficult to manipulate and are not conducive to laboratory studies.
"Fruit flies, on the other hand, are a geneticist's best friend. There are many genetic markers, we can conduct genetic screens simply and in large numbers, and we now have the complete sequence of the fly genome," says David Schneider, a Fellow at the Whitehead Institute and the lead author of the study.
These characteristics have made the fruit fly an excellent model to study human diseases, but Schneider suspected that it would also make an ideal model mosquito.
Schneider tested this hypothesis in collaboration with Mohammed Shahabuddin, of the National Institute of Allergy and Infectious Disease. Schneider injected a form of Plasmodium, the parasite that causes malaria in chickens, into the body cavity of the flies. When he allowed the carrier flies to infect chickens, the birds developed full-blown malaria. He also observed that a component of the fly's immune system, known as a macrophage, was able to destroy Plasmodia in an attempt to fight the infection. These results suggest that the fruit fly can indeed serve as a model for studying malaria parasite development.
In carrying malaria, mosquitoes do not act merely as dirty hypodermic needles, passing infected blood from one person to another. Instead, they provide an environment for the parasite to grow and develop. The parasite enters the mosquito when the mosquito bites an infected person and drinks a "blood meal." Once inside, the parasite undergoes a two-week growth phase and then is transmitted to a new host when the mosquito takes a second blood meal.
By learning more about the factors that enable the parasite to grow inside the mosquito host, Schneider hopes that scientists will be able develop new ways to treat and prevent the spread of malaria.
"One advantage of using fruit flies instead of mosquitoes is that we can do large-scale genetic screens to find mutants," says Schneider. "We can knock out genes to determine whether the parasites grow better or worse when a particular gene is missing." By identifying factors that are critical to the parasite's survival inside the mosquito, these experiments may lead scientists to drugs that prevent the parasite from growing in the mosquito. Weak points in the parasite's lifecycle could be potential targets for anti-malarial drugs and vaccines.
Because parts of the human immune system are very similar to the immune systems of flies, this approach will also help scientists understand how we fight infection and will hopefully lead to new ways to treat malaria. One particularly vexing aspect of the Plasmodium parasite is that it becomes resistant to antibiotics very quickly.
"The first drugs used to treat malaria were inexpensive and had few side effects, but they are no longer effective because the parasite has become resistant," Schneider explains.
In fact, chloroquine resistance continues to increase in Africa, and with fears of toxicity and decreased efficacy for sulfadoxine/pyrimithamine, the World Health Organization has declared that there is an urgent need for an affordable, effective, and safe alternative to chloroquine. "The alternative drugs available today are very expensive and not a viable option for the vast majority of people suffering from malaria, who happen to live in some of the world's poorest countries," Schneider says.
Another possibility is that a better understanding of how mosquitoes carry malaria might lead to a transmission-blocking vaccine. Malaria vaccines have been particularly elusive because Plasmodium hide inside human cells, making it difficult for the immune system to locate and purge it from the body. Furthermore, the parasite acts like a chameleon, constantly changing its surface so the immune system is unable to recognize it.
A transmission-blocking vaccine would not protect the person who originally becomes infected with malaria. Instead it would prevent the disease from spreading throughout an entire village by prohibiting the parasite from developing inside the mosquito.
Much further down the line, the fly model might also be useful in creating mosquitoes that are resistant to malaria. Theoretically, these designer mosquitoes could be released into the wild where they would replace the vulnerable native mosquitoes. "By understanding how the host mosquito fights the malaria infection, we might be able to design mosquitoes that fight harder," Schneider adds. "We're a long way from changing the genetic make-up of mosquitoes in such a drastic manner, but it may be a very real possibility in the fight against malaria in years to come."
The title of the paper is "Malaria Parasite Development in a Drosophila Model." The authors are David Schneider of the Whitehead Institute and Mohammed Shahabuddin, of the National Institute of Allergy and Infectious Disease. Schneider's research was supported wholly by the Whitehead Institute. Shahabuddin's research was supported by the John D. and Catherine T. McArthur Foundation.
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