In the popular perception, leishmaniasis is an endemictropical skin disease that afflicts only poor people faraway.
But in the Sudanese republic, where an endless civil warcontinues to convulse society, the World HealthOrganization reports that literally hundreds of thousandsof people are dying from an outbreak of a particularlydeadly form of the infection.
A map of the world depicting global spread ofLeishmania, the parasite that causes leishmaniasis, alsowill highlight the home turf of a small, biting wingedinsect, the sandfly. Because sandflies infest much of LatinAmerica, Africa, south Asia and the Mediterranean basin,so does leishmaniasis.
Sandflies live on mammalian blood. Leishmania live on,or rather in, sandflies. They hole up on the wall of theinsect's midgut, and exit with its bite into thebloodstream of its victim. Eventually it winds up insideof that blood's macrophages _ scavenger cells with themission of digesting and expelling foreign or superfluousorganisms and particles.
Not, however, the Leishmania invaders. These snuggleinto the macrophages, resisting their digestive juices, andbegin to multiply inside their lysosomes. Sooner or laterthis proliferation bursts open their host cell, sending theparasites forth to hijack more macrophages, until anothersandfly bite closes the loop of their life cycle.
Inside their human host, the Leishmania cause severe skinulcerations, as well as internal symptoms of varyingseverity. One variant, visceral leishmaniasis, penetratesmacrophages of liver and spleen, with usually fatalresults, as in the Sudan.
What accounts for Leishmania's virulence? And what canbe done about it? Tackling those questions is a full-timeoccupation for molecular geneticist Stephen Beverley andhis research fellows at Harvard Medical School'sdepartment of biological chemistry and molecularpharmacology.
In last week's issue of Science, dated Sept. 29, 1995, theteam reports its progress to date. Their paper bears thetitle: "A specialized pathway affecting virulenceglycoconjugates of Leishmania."
Virulence Factor, In Its Time, Plays Many Parts
Its co-authors, using genetic complementation, have justidentified a gene that encodes an enzyme responsible forsynthesis of a virulence determinant in the parasite. Thisis a complex, cell-surface glycolipid, lipophosphoglycan(LPG), which Beverley calls "a very interestingmolecule." LPG's interest lies partly in its extravagantextracellular structure, but mainly in its sinisterversatility.
The first of its many roles in Leishmania's life cycle is tobind the parasite to the sandfly's digestive tract wall."Then, at some point," Beverley told BioWorld Today,"when the fly has digested its blood meal, and is ready tomake its next bite, the parasite modifies its LPG in a verysubtle way that causes it to release its hold on the insect'smidgut wall, and permit its transmission to its prey withthat next bite."
But this only scratches the surface of LPG's proteanperformance. When the parasite enters its victim, itencounter's the body's first-line immune defense, in theform of the complement system. Complement's job is topunch lethal holes in invading microbes, but Leishmaniaturns the tables, and resists its lytic attack. "This is veryimportant," Beverley observed, "because otherwise it'sdead."
Then, as the parasites break and enter the macrophage,LPG acts to tranquilize or paralyze this host cell, thusfoiling its built-in urge to kill off and expel the invaders.
"LPG is essential for the infection of humans, but not forits growth in vitro" parasitologist Albert Descoteaux, thepaper's first author, told BioWorld Today.
To lay bare the tactics and strategies of this all-purposebodyguard molecule of virulence, the team appliedchemical mutagens to make mutant Leishmania, devoidof LPG protection.
Using these LPG-minus mutants, Beverley explained,"we were able to dissect the glycolipid's functions, andidentify the genes responsible for its synthesis. Some ofthese," he added, "show potential as targets fortherapeutic intervention."
Such intervention, he indicated, could take any of threestrategic forms: inhibition, chemotherapy or prophylaxis_ vaccines.
Inhibiting LPG synthesis, Beverley observed, "wouldseem like a pretty good idea for trying to control theparasite." In favor of this ploy "is the fact that we humansdon't have in our bodies anywhere near the equivalent ofan LPG molecule."
On inhibition's downside, he continued, is the fact that"inhibitors are not the same thing as drugs. You have toget them into cells, make sure they have the appropriatepharmacokinetics, limit their side effects. All of whichmakes for a very slow drug-development process."
Slowing the process still further beyond thepharmacological aspect, Beverley observed, is that "themarket is often not considered to be all that substantial,because of its population's poverty. He explained:"Rarely are individual people buying these anti-parasitedrugs. Usually it's governments of relatively poordeveloping countries. But in aggregate, with theassistance of international health bodies, there is enoughof a market there so that it shouldn't be a no-fundingsituation, I guess."
A possible exception to this dismal outlook, he added, isthe Leishmania threat in several industrialized countriesbordering the Mediterranean, namely, Spain, Portugal andthe South of France.
Leishmania's French Connection: AIDS
"There," he said, "a form of visceral leishmaniasis infectspeople, who usually remain asymptomatic unless theybecome immunocompromised. Then the infectionreactivates very severely. Of course," Beverley pointedout, "in that part of the world this now makesleishmaniasis an opportunistic AIDS infection. So," hesuggested, "The interest from pharmaceutical companiesin the developed world is more intense around theMediterranean."
His laboratory continues to "turn up a lot of genes andenzymes that are going to have good potential as drugtargets. In some cases," he said, "they might even havepotential not only against Leishmania but for other sortsof pathogens," thanks to a novel shared virulencepathway not present in humans.
Among these are the mycobacteria, which causetuberculosis and leprosy. "Mycobacteria would be afantastic target," Beverley observed, "if we could use ourLeishmania work to go into this particular tuberculosispathogen, which is very widespread, even in the U.S."
His group is now making LPG-minus knockoutLeishmania parasites, with the prospect of "veryinteresting properties." For example, Beverley concluded,"let's say they were able to successfully invade amacrophage, but were no longer able to survive there. Inthe process of doing that, they would be presenting theirproteins and lipids and whatevers to the immune system.So there's a chance that some of these knockouts willhave potential for making a vaccine." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.