By David N. Leff
Say you're a tourist just back from a big game safari in Kenya or Tanzania.
Those antelope you may have been shooting, with gun or camera, are natural meal tickets for the tsetse fly (Glossina species), which in turn is a meal ticket for trypanosomes, the parasites that carry human sleeping sickness.
Unlike anopheles mosquitoes, which deliver malarial parasites with only a slight itch at the site of their bite, the stab of a tsetse fly's proboscis is so painful, you'll know you were bitten. And if the tsetse bite site develops into a red chancre sore, surrounded by a waxy white halo, you can be sure your system is playing host to a dose of rapidly multiplying sleeping-sickness parasites.
But not to worry. At this early stage of infection, modern Western medicine and hospitalization can probably pull you out of the trypanosomiasis, by means of drastic chemotherapy.
Fifty million people in sub-Saharan Africa are less lucky. They inhabit the 36-nation sleeping sickness belt across the continent's midriff, which is home to Glossina, the vector of trypanosomiasis.
Recent figures from the World Health Organization put at 100,000 the number of people infected with African sleeping sickness at any given time, and 20,000 the number who die of trypanosomiasis each year. Many tropical disease specialists regard these statistics as "gross under- estimates."
Among them is molecular parasitologist Stephen Hajduk, a professor of biochemistry and molecular genetics at the University of Alabama, in Birmingham.
"About seven to 10 million head of cattle a year die of ngana," Hajduk told BioWorld Today, "which is caused by a genetically identical form of the trypanosome parasite. And it's spread by exactly the same insect vector, the tsetse fly."
Hajduk observed that "Certainly from an economic and probably human-impact standpoint, ngana is much more important. It's the major veterinary disease in Africa."
After the human immune system rushes host defense cells to the fly-borne injection of trypanosomes, causing the initial skin chancre, the parasites begin their leisurely pilgrimage to lymph nodes to blood stream to central nervous system (CNS). At first, they produce familiar flu-like symptoms, such as mild headaches and fever.
Then, six or eight weeks later, the parasites invade the CNS, "by a mechanism," Hajduk said, "that's totally unknown. But the patients tend to lapse into a complex series of neurological problems and psychoses, after the CNS is infected.
"Several months later," he went on, "comes the sleeping-sickness stage, in which the patient becomes semi-comatose, and goes into periods of uncontrolled sleep."
Trypanosomiasis: An AIDS-Like Malady
At this point, the disease takes on a weird resemblance to AIDS. Malnutrition increases; the immune system is suppressed. There's an over-all cachectic response of body wasting, due to the induction of tumor necrosis factor (also known as cachectin), and such-like cytokines. Death is usually caused by a secondary opportunistic respiratory infection.
"Human sleeping sickness," Hajduk pointed out, "is inevitably fatal. It probably ranks as one of the few diseases where, untreated, you die. The treatments," he added, "are problematic. That's what got us involved in studying these trypanosomes."
Today's issue of Nature, dated Feb. 27, 1997, reports a signal discovery his studies have yielded, to wit: "Mechanism of resistance of African trypanosomes to cytotoxic human HDL."
Human high-density lipoproteins, HDLs, are best known as the "good-guy" molecules that serve the body as cholesterol bouncers.
Hajduk's research led him to the finding that a subclass of HDL carries a toxin that circulates in the blood, called human haptoglobin-related protein. This cell-lysing substance has the gift of killing Trypanosome brucei brucei, the tsetse-spread parasite that inflicts fatal ngana on African cattle.
"If it's so bloody potent at killing the veterinary forms of the parasite," Hajduk said, "how on earth are the human sleeping sickness trypanosomes — which we think are genetically identical to the ones that cause the disease in cattle — able to resist the lethal activities of this innate HDL killing factor?"
Hajduk traces the toxin's "pathway of death" in the ngana parasite: "It would have to be bound to the trypanosome cell's surface, trafficked inside the cell, then taken to its digestive vacuole, the lysosome, which kills it."
Target Takes Detour On Path To Death
The way the human parasite circumvents this terminal outcome, Hajduk continued, "is by still binding the toxin very tightly, probably to the same surface receptors as the veterinary version, but it's no longer taken in.
"So it sits on the surface; it's not endocytosed. And it never hits the digestive vacuole, which is the active site for this toxin. And as a consequence, the parasite is able to live on."
Hajduk is now "trying to identify why that human sleeping sickness trypanosome is able to sequester the toxin on its surface, and not bring it into its cell. "We have identified some of the parasite's genes, which appear to be involved in this," he said.
But sequestration is not the only life-saver in trypanosome's bag of tricks. "Our biggest problem as far as treatment is concerned," Hajduk recounted, "is really VSG * variant surface glycoprotein. This molecule is anchored in very high numbers — probably on the order of a billion copies — on the cell surface. It coats the entire trypanosome, and the parasite can change this surface coat in a semi-random fashion, while it's infecting the host."
Hajduk continued: "This allows the parasite to change its presentation to the host's immune system. Of approximately 1,000 genes in this VSG coat, it turns on one at a time — making one protein molecule, but lots of it, covering the entire surface of the trypanosome.
"If the host mounts an immune response against the trypanosomes during the infection, whether in man or in animals, most of the parasites are killed. But the few that have already spontaneously changed their VSG type, are not recognized by the immune system.
"So those grow up, and present another wave of parasites to the host's immune system, which very quickly says: 'Oh, here's something else.' So it makes another set of antibodies, and activates another set of cells for another immune response.
"The human immune response," Hajduk observed, "is very effective against each one of those waves. The problem is that there's a thousand different ways that the trypanosome can coat itself. As a consequence, this makes it impossible for us to develop vaccines.
"There's zero likelihood that we'll see a vaccine against African sleeping sickness, and it's mainly because of this parasitic process of antigenic variation."
Instead, he concluded, "we've taken the human gene for the HDL toxin, and made transgenic mice that can tolerate its expression, and which make the HDL toxin." His next step is to challenge those animals with live trypanosomes, on the way to making them resistant to trypanosomiasis. *