Editor's note: Science Scan is a roundup of recently published biotechnology-relevant research.
For decades, malariologists have been constructing and field-testing vaccines designed to protect people against the likes of malaria's deadliest pathogen, Plasmodium falciparum. Their strategy continues to center on educating immune system antibodies to zero in on key target antigens in P. falciparum's various life stages.
Have these dogged vaccinologists been barking up the wrong tree? Can their strategy be neat, plausible and conceptually wrong? Indifferent results of unending field-tested vaccines over the years suggests so.
Australian immunologists at the reknowned Walter & Eliza Hall Institute of Medical Research propose an entirely different bull's eye - a toxin released by the parasite, rather than an antigen. A mouse malaria model bears out this conjecture, as reported in Nature dated Aug. 15, 2002, and titled: "Synthetic GPI as a candidate anti-toxic vaccine in a model of malaria."
Their paper leads off by making the point, "The malaria parasite Plasmodium falciparum infects 5 [percent] to 10 percent of the world's population and kills 2 million people [mostly children] annually. Fatalities are thought to result in part from pathological reactions initiated by a malarial toxin."
This lethal toxic compound is GPI - glycosyl phosphatidyl inositol, a carbohydrate. "As anti-toxin vaccines can be highly effective public health tools," their paper continues, "we sought to determine whether anti-GPI vaccination could prevent pathologies and fatalities in the Plasmodium berghei rodent model of severe malaria." The team chemically synthesized this GPI toxin and used it to immunize mice. At the same time, they verified that anti-GPI antibodies neutralized pro-inflammatory activity by P. falciparum in vitro.
"In contrast to acquired clinical immunity," the Nature paper points out, "anti-parasite immunity takes many years to develop and is easily lost, reflecting the problems of antigenic diversity . . . immune evasion strategies . . . in the immune response to parasite antigens." It goes on to argue, "Current approaches to anti-malarial vaccines seek nonetheless to induce anti-parasite immunity through parasiticidal mechanisms targeted to parasite protein antigens. The public health potential of alternative anti-disease vaccine strategies is demonstrated by the highly effective tetanus and diphtheria toxoid vaccines that protect against . . . infection by targeting bacterial toxins."
The authors conclude in their paper, "GPI may contribute to pathogenesis and fatalities in humans. Synthetic GPI is therefore a prototype carbohydrate anti-toxic vaccine against malaria." However, they also note that "indeed the toxic basis of malarial pathogenesis, first conjectured by Camillo Golgi [1843-1926, a pioneer microscopist] in 1886, remains unproven."
Malarial Parasite Feels The Heat As It Commutes From Mosquito To Human
On another page in the same issue of Nature, dated Aug. 15, 2002, parasitologists at NIAID, the National Institute of Allergy and Infectious Diseases in Bethesda, Md., report taking Plasmodium falciparum's temperature. They show that "thermoregulation, in which the transcription of select RNAs is upregulated at cooler temperatures, is crucial to the development transition that occurs during the transmission of P. falciparum from human to mosquito. Their Brief Communication carries the title: "Thermoregulation in a parasite's life cycle."
Excess Plasminogen Activator In Rabbits Paradoxically Enhanced Atherosclerosis Risk
A common treatment for blood clots may actually worsen atherosclerosis if it's supplied in excess through gene therapy. An in vivo experiment using rabbits found that overexpression of a plasminogen activator in blood vessels hastened the effects of atherosclerosis - narrowing arteries. This disorder, better known as hardening of the arteries, causes vessel walls to thicken and constrict, thus reducing flow blood and heightening the risk of a heart attack. Plasminogen activators are drugs that purge clots from the pinched arteries.
A paper in the Proceedings of the National Academy of Sciences (PNAS), released July 29, 2002, is titled: "Increased expression of urokinase [a type of plasminogen activator] during atherosclerotic lesion development causes arterial constriction and lumen loss, and accelerates lesion growth." Its authors are cardiovascular specialists at the University of California at San Francisco.
They had previously found that using gene therapy to overexpress urokinase inside the arteries' endothelial cells themselves targeted its clot-busting effects without risking bleeding at other locations. They then designed an experiment to test the effects of excess urokinase on vessel walls. They cloned a rabbit urokinase complementary DNA and expressed it in carotid arteries of cholesterol-fed rabbits. Four weeks later, they were surprised to find the vessels constricted, not relaxed, and growth of early atherosclerotic lesions enhanced.
They point out that their in vivo experiment differs significantly from current clinical practice, suggesting that there is no immediate cause for concern.
Nitric Oxide's New Enzyme-Jazzing Pathway Hints At Treating Neurodegenerative Diseases
Nitric oxide (NO), an ephemeral gas produced in the body, and an air pollutant, has found a new gig: It can activate enzymes outside nerve cells to trigger their demise during stroke and neurodegenerative diseases such as Alzheimer's, multiple sclerosis and AIDS dementia. When these NO enzymes are overactivated, they chew up the exterior of neurons, causing them to die.
A paper in Science, dated Aug. 18, 2002, reports this finding under the title: "S-Nitrosylation of matrix metalloproteinases: Signaling pathway to neuronal cell death." Its senior author is neurologist Stuart Lipton at the Burnham Institute in La Jolla, Calif., which sponsored the research. "Now that we know about this new pathway to neuronal death that occurs outside the cells," Lipton observed, "we can design drugs to interrupt it." He and his co-authors are starting to test such agents in rodent models of stroke.
Multiple molecular pathways contribute to brain damage in human stroke patients. One of these is the gaseous NO neurotransmitter. Its release in excess leads to stroke damage.