By David N. Leff
Anti-ballistic missiles, originally conceived as the ultimate Cold War weapon, nowadays are described as shields against terrorist attacks by so-called "rogue" nations - notably, Iraq, Iran and North Korea.
This week in Geneva, the International Red Cross arraigned three global diseases as far more deadly than mere military warfare. Specifically, it singled out AIDS, tuberculosis and malaria as having killed 150 million people since 1945, compared with 23 million war dead in that period.
TB's mycobacterium, the AIDS virus and the malarial parasite are rogue pathogens in every sense of the word. Malaria alone kills well over 1 million people a year - most of them children - and infects half a billion. Decades of research have come up with candidate vaccines, none of which so far has proven effective against the slippery pathogenic protozoan parasite, Plasmodium falciparum. Worse still, the low-cost antimalarial drugs, beginning with quinine and peaking with chloroquine, are fast losing their battle against the parasite's multidrug-resistance genes.
Propelling this death-dealing missile is P. falciparum's hyper-sophisticated delivery system - the Anopheles gambiae mosquito. That insect and its parasitic payload are literally made for each other. When the mosquito lands on a patch of malaria-infected skin, it tanks up on human blood and buzzes off with a gulp of the blood-borne P. falciparum parasite. Inside the insect's belly, this versatile microorganism goes through a series of transformations and in a couple of weeks delivers a fresh batch of parasites to Anopheles' salivary glands. So the next time the mosquito bites human prey, it pumps in a new dose of infectious parasites. (See BioWorld Today, Feb. 24, 2000, p. 1.)
Insect biologist David Schneider, at the MIT-affiliated Whitehead Institute in Boston, specializes in the world's first and foremost insect model, namely the fruit fly, Drosophila melanogaster. Some years ago he recruited D. melanogaster to take on a new gig - understudying malarial mosquitoes.
"As a Drosophila geneticist," Schneider recounted, "I studied the fly's immune system. When most researchers do that, they use the insect as a model human. I started looking to use the fly as a model vector for disease. Malaria was the one I came to quickly because it was most important, and also carried by an insect, the mosquito, that's reasonably similar to the fly."
Malarial Parasites As Fly Specks
"About two and a half years ago," he went on, "I contacted some malaria people at the National Institute of Allergy and Infectious Diseases. There, parasitologist Mohammed Shahabuddin invited me to try some experiments. They worked the first time; it was terrific."
Schneider and Shahabuddin are, respectively, first author and senior author of a paper in today's Science, dated June 30, 2000, which brings their joint research up to date. Its title: "Malaria parasite development in a Drosophila model."
"Almost everything that's in that Science article," Schneider told BioWorld Today, "I started right then. We tried every way we could think of to infect fruit flies with the malarial parasite. We fed them infected blood. We fed them purified parasites, and we injected parasites into their bodies. It turned out that the parasite only developed when we injected it into the body cavity of the fly.
"Our goal," he continued, "is to come up with a system where we can use the power of Drosophila genetics to study host-pathogen interaction. We hope to understand what nutrients an insect gives to the pathogen growing inside it. And also how the insect's immune system fights the parasite.
"We chose to do this in the fly," Schenider explained, "rather than in the mosquito, because there are so many genetic tools available in the fly. And now that Drosophila's genome has been sequenced, in March of this year, even if we're working with a surrogate insect model I think there are things we can learn faster by doing it in the fly first, then jumping to the mosquito."
But at this stage, not the Anopheles gambiae mosquito nor the Plasmodium falciparum parasite. Instead, Schenider and his co-author are infecting their fruit flies with Plasmodium gallinaceum, which inflicts lethal avian malaria on chickens. "The advantage of the chicken parasites," Schneider pointed out, "is that chickens are a lot bigger than mice. So we get a lot more blood out of them." And instead of Anopheles, their mosquito of choice is the wieldier Aedes aegypti, which bites birds in the laboratory and infects them with P. gallinaceum.
Chickens they infected with their fly-grown P. gallinaceum developed malaria and transferred the parasites to susceptible Aedes mosquitoes when those insects fed.
Armed with the results of their fly experiments - which show that chicken-programmed malarial parasites largely simulate the life cycles of antihuman P. falciparum - the co-authors now are beginning to think of vaccines. "One type of antimalarial immunization agent our findings would help us make," Schneider suggested, "is transmission-blocking vaccine. That's vaccine that doesn't work in our body; it works in the mosquito's body. The mosquito drinks in the antibody with its blood meal, then the antibody works on the parasite inside the mosquito. In order to get something like this to work, we'd like to understand how the parasite and mosquito interact so we can find out what antibodies we should make to interfere with this interaction."
Vaccines, Antibiotics, 'Not Around Corner'
"A transmission-blocking vaccine would not protect the person who originally becomes infected with malaria," Schneider pointed out. "Instead, it would prevent the disease from spreading throughout an entire village by prohibiting the parasite from developing inside the mosquito.
"There is a vaccine that works this way already," he added - "the Lyme disease vaccine is a transmission-blocking vaccine." But Schneider made the point, "Such an antimalarial vaccine is by no means around the corner. We still have to learn the biology. We're at the point now where we're trying to find antibody targets."
To crack the parasite's other weapon - multidrug resistance - Schneider went on, "We are trying to learn how insects kill the parasites, which they can do quite effectively. This might tell us some weaknesses in the parasites - giving us ideas for drug targets. We are screening to find mutant flies in which parasites don't survive. That could tell us what nutrients are essential for the development of parasites and lead to drugs that would block those pathways."