By David N. Leff
Two of the world's most devastating - and different - tropical diseases have just been caught in an unsuspected dangerous liaison. It turns out that malaria and Chagas disease both drink from the same poisoned chalice that threatens them after a hearty feast on human blood.
Malaria, as all the world knows, cuts a wide swath of death and debility all around the globe's midriff. Its blood-sucking insect cutout is the Anopheles mosquito, which injects Plasmodium parasites into the wound it bites in its victim's skin. After a stopover in the liver, where it multiplies mightily, the parasite beelines to the circulation's red blood cells, from which another mosquito picks it up for the next round of infection.
Chagas disease is mainly prevalent in broad areas of Latin America. Its insect blood-suckers are big bugs, notably the inch-long Rhodnius prolixus, known in Portuguese and Spanish as the equivalent of "assassin bug" or "kissing bug."
Brazilian biologist and biophysicist Marcus Oliveira tells why: "Kissing bug, because the insects are able to suck the blood of humans from biting the face and mouth generally, of people who live in Brazil's countryside." A single bug can digest several times its own weight in blood during one meal. In Brazil," Oliveira added, "we have thousands of cases of Chagas disease." (See BioWorld Today, April 3, 1997, p. 1.; and May 8, 1998, p. 1.)
It was a Brazilian physician named Carlos Chagas (1879-1934) who gave his name to the malady, and described its mode of attack. When R. prolixus, or other bugs of its ilk, alight on a victim's face, and bites, after sucking the blood, it turns tail, as it were, and deposits its feces into the wound. The excreted contents of its intestines swarm with a protozoan parasite called Trypanosoma cruzi, which is to Chagas disease what Plasmodium is to malaria.
The mayhem that T. cruzi wreaks is less lethal than malaria's, but its pathological consequences can last a lifetime. "Chagas patients," Oliveira noted, "usually exhibit symptoms a long time after infection, but in endemic areas 20 percent of infected people develop cardiomegaly - their heart becomes enlarged. And so does their esophagus and gut get larger. Then, after infection with T. cruzi, severe complications of the cardiovascular system occur, as well as many other symptoms," including encephalitis. There is no cure.
Pathogens Polymerize Heme Poison Antidote
Oliveira, a postdoctoral fellow in the department of biochemical medicine at Brazil's Federal University of Rio de Janeiro, is lead author of a paper in today's issue of Nature, dated Aug. 5, 1999. Its cryptic title reads, "Heme detoxification by an insect."
"Heme," Oliveira explained, "is a part of the hemoglobin molecule, the part that transports oxygen. In malaria, Plasmodium parasites detoxify most of the heme by polymerizing it into an insoluble polymer called hemozoin. And this step of polymerization," he pointed out, "is a target of many antimalarial drugs.
"In our Nature paper," Oliveira told BioWorld Today, "we show for the first time that this process also occurs in the blood-sucking insects, in Rhodnius prolixus. And this finding, we believe, can bring new ideas of new therapies for malaria. Also we emphasize that this polymer could be an important way for the Rhodnius insects to avoid heme toxicity."
He made the added point "that this involves a strong relationship between the hemazoin polymer and the T. cruzi Chagas parasite, because T. cruzi live inside the midgut of these insects, which is the place where a lot of this hemozoin polymer exists. And in a free form," he went on, "after digestion of hemoglobin in blood-sucking insects, heme, which is very toxic, is released free in solution. So the Rhodnius bug has to deal with that higher amount of heme."
Oliveira spelled out the significance of this new finding: "Probably it means that blood-sucking insects, and the parasites of blood in general, have the same way to deal with high amounts of heme polymer digestion. Not only Plasmodium, not only Rhodnius, but probably other hematophagous animals have to cope with higher amounts of heme. They resolve this problem by polymerizing heme to hemazoin, in order to avoid heme toxicity, which is a serious problem in these insects. Heme in a free state in solution," Oliveira pointed out, "is very toxic, because it generates free radicals, which are able to oxidize many molecules. So keeping heme in inert polymeric form could avoid this toxicity."
Oliveira added, "We are now investigating the protective effect of hemazoin to Rhodnius, studying the question: 'Is there really a less toxic form of heme?' So we are doing experiments comparing the toxicity of heme in a monomeric form with polymeric hemazoin from the insect. Our first results," he concluded, "suggest that hemazoin in the bug is really less toxic."
New Route To Disrupting Hemozoin Synthesis
A former collaborator of the Brazilian co-authors is Josi Ribeiro, now a section chief in the Laboratory of Parasitic Diseases at the National Institute of Allergy and Infectious Diseases (NIAID) in Bethesda, Md. Commenting on Oliveira's paper in Nature, Ribeiro told BioWorld Today: "The interesting aspect is that you have two completely different organisms. One, an insect that feeds on blood, of which the highest component is hemoglobin. And the other, a parasite that infects the red cell. Both have this problem of detoxifying heme, and both have converged to the same mechanism of creating hemozoin.
"In a more general aspect," Ribeiro continued, "I think it emphasizes how insects in their enormous biodiversity can adapt any thinkable biochemical pathway to exploit a particular niche in the environment."
Anent Oliveira's suggestion that new antimalarial drugs may emerge from their finding, Ribeiro observed, "I think what they are probably talking about is the mechanism of hemazoin formation, which is not completely known in Plasmodium, but which chloroquine, one of the most potent antimalarial drugs, apparently disrupts. So from a basic perspective, understanding more about this, now you have another model to tinker with, that may be even more robust.
"The authors point to a mechanism that could initiate the hemazoin formation. So you would have another system to look at hemazoin synthesis, and the possibility of its disruption. That actually could be tested in the malarial parasite itself."