OXFORD, England -- Researchers seeking to develop a vaccinefor malaria must first characterize and clone some of thepathogen's rapidly changing genes.
Malarial blood parasites switch their antigenic disguises withunexpected speed to evade their human victims' immunedefenses, according to a report Thursday in Nature. In their redblood cell hideouts, more than 2 percent per generation of thepathogens take on new antigenic profiles for latching ontoblood vessel walls.
"Adhesion of parasitized erythrocytes to post-capillary venularendothelium or unaffected red cells is strongly implicated inthe pathogenesis of severe Plasmodium falciparum malaria,"said the paper, whose lead author is David J. Roberts of theRadcliff Hospital's Molecular Parasitology group here. He andhis co-workers found that the genes that code for thepathogen's adhesion to its target cells undergo variation at amean rate of 2.4 percent every 48 hours, keeping severaljumps ahead of their host's defending antibodies.
"If and when these genes can be characterized and cloned, abasis will exist for developing a vaccine against this fast-feinting immune target," the group's director, Christopher I.Newbold, told BioWorld.
"Modulation of receptor phenotypes in cloned parasites isdescribed here for the first time," said Russell J. Howard of theDNAX Research Institute of Molecular and Cellular Biology inPalo Alto, Calif. These "asexual deviants" of P. falciparum cells"can vary the antigenic phenotype of the infected red blood cell(RBC) surface antigen and the specificity of (their) surfacereceptor(s) for adherence to host cells at an alarmingfrequency."
P. falciparum, the deadliest of the malarial protozoan's fourmain species, infects 200 million to 400 million people everyyear and kills 1 million to 4 million people, mostly children,said David C. Kaslow, a malariologist at the Molecular VaccineSection of the NIH's National Institute of Allergy and InfectiousDiseases. He is developing a vaccine to block transmission frommosquito to man.
When a female Anopheles mosquito bites a victim, it injects acolony of parasites that have been growing as sexual-phasegametocytes in the insect's gut. The now-asexual sporozoitesenter the liver from the bloodstream and emerge in a week orso as merozoites to attack circulating RBCs, in which theyreproduce asexually. The parasites break out of the RBCs,causing the clinical crisis in the malaria patient, and hunt fornew RBCs.
A normal, uninfected RBC lives about 120 days before it isabsorbed by the spleen, which recognizes and removesmalaria-infected erythrocytes. But P. falciparum evades thiswaste-disposal threat in two ways. First, the pathogen activatesgenes that express receptors for endothelial cells that line theblood-vessel walls. Infected red cells adhere to these, andavoid passage to the spleen. In addition, the antigenic diversityand variation of the parasite enables some of them to sidestepthe antibodies in the human immune system. P. falciparum isalso quickly developing worldwide resistance to chloroquine,the most effective anti-malarial drug currently available.
The Oxford group first separated out a single blood-stageparasite from which they grew 27 progeny clones, all with thesame genetic endowment. They discovered that the clonedparasites spontaneously expressed 10 new surface-antigenphenotypes and modulated receptor phenotypes.
"Their pronounced and protean rosetting capability isconcomitant with severity of the disease and pathologicallysignificant," Newbold said.
He added that his laboratory is trying to clone the genesencoding the parasite's quick-switching antigens. "This work ishampered by our group's lack of any monospecific reagents forthis great diversity of molecules, all of which are larger than200 kiloDaltons," he explained. "We have no handle on theconserved regions. Meanwhile, we continue to investigate themolecular interaction of host-cell receptor and the pathogens."
David N. Leff, BioWorld's new science editor, foundedBiotechnology Newswatch for McGraw-Hill in 1981 and was itschief editor until 1990.
-- David N. Leff Science Editor
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