You may remember the parable of the ingenious patriot who inventedan armor-plating against which all known projectiles would bounceoff harmlessly. Next he patented a projectile that could pierce thisplating, then formulated a coating to make the armor projectile-proofand so on.
When the ingenious patriot offered to license his proliferatinginventions to the king, the monarch issued a retroactive decreemaking ingenuity a capital offense.
Such a death penalty marks the escalating duel between thecompeting ingenuities of the malarial parasite, Plasmodiumfalciparum and the scientists seeking to scotch its depredations. Sofar, P. falciparum seems to be winning the battle.
The World Health Organization puts at 300 million the number ofpeople infected by the malaria parasite, which it estimates kills wellover 1 million a year, mostly children.
Besides slaughtering these innocents, P. falciparum blunts themedicinal weapons raised against it. Drug after anti-malarial drugfalters and falls to its ingenious resistance factors. The latest to peterout is chloroquine. (See BioWorld Today, Sept. 26, 1995, p. 1.)
When a mosquito delivers a dose of plasmodia through the skin of ahuman victim, the hungry parasites make first for the liver, then forthe unwitting host's red blood cells.
"Once inside a red blood cell," molecular parasitologist DanielGoldberg said, "an individual parasite grows at a prodigious rate overthe next two days. It degrades the cell's hemoglobin as a majorsource of nutrient for its growth and maturation.
"During this degradation process," Goldberg said, "heme is releasedfrom inside the hemoglobin molecule."
Heme is the nonproteinaceous part of the hemoglobin molecule. Itcarries the atoms of iron that make red blood cells red, and distributethe blood's freight of oxygen.
Heme is life-giving to humans but toxic to malarial parasites. "Sowhat P. falciparum does," Goldberg continued, "is detoxify the hemeby polymerizing it to an insoluble, crystalline polymer calledhemozoin."
On day one after invading a red blood cell, the parasite feasts on theglobin protein left after it has turned the heme into solid waste. Itgrows so big that it takes over almost the entire red blood cell. "Then,on the second day," Goldberg went on, "it multiplies, dividing itsnuclear material into 16 to 32 small packages. Each one of these isnow a separate organism, which will burst out of the red blood celland attack new red cells."
Goldberg, a Howard Hughes Medical Institute investigator, runs thePlasmodium laboratory at Washington University, St. Louis. He issenior author of a paper in today's Science titled: "Plasmodiumhemozoin formation mediated by histidine-rich proteins [HRP]."
"What we have now shown," he told BioWorld Today, "is that afamily of proteins rich in the essential amino acid histidine mediatesthis polymerization of heme to hemozoin. The key to the puzzle isthat this bizarre histidine-rich protein is unique to the malariaparasite."
That richness takes the form of multiple histidine repeats in the HRP."We don't understand yet," Goldberg observed, "how these repeatamino acids are represented in the protein's three-dimensionalstructure. That's something we're working on. But having multiplehistidines like that is associated in other systems of the body withability to bind hemes."
He and his co-authors isolated from the parasite's 20-megabasegenome a one-kilobase gene that encodes an HRP. "That was asurprise to us," Goldberg said. "HRP has been known for quite awhile. It was thought that the parasite secretes this protein into itshost red blood cell's cytoplasm." They found that indeed it does so,"but then sucks it in as it's ingesting the hemoglobin."
Other genes of interest that the team characterized in the parasite'sdigestive vacuole (a lysosome-like organelle in its feeding system)encodes one of the proteases that degrade the hemoglobin. "Thisactually belongs in the same class," Goldberg observed, "as the HIVprotease."
He added: "What we found there is that the parasitic protease attacksnative hemoglobin and unwinds it. It cleaves it in a strategic spot andunravels it. This lays it open so that further proteolysis _ which iscritical for this massive degradation _ can proceed efficiently.
"We are currently designing inhibitors," Goldberg said, "that blockthis degradation and effectively starve the parasite to death."
Chloroquine, now on the endangered-species list of antimalarialdrugs, because of plasmodial resistance factors, "appears to work,"Goldberg observed, "by concentrating in P. falciparum's digestivevacuole, and blocking the polymerization and detoxification of heme,which then kills the parasite. Now that we understand how thisoccurs, we should be able to develop better chloraquines."
He added: "We should also like to develop drugs that attack the samecrucial target that chloraquine does, but are not susceptible to themodes of resistance that the parasite has come up with. We havesome early leads but it really is the early stages." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.