Of the 400,000 American troops who fought in the Gulf War, a dozensoldiers returned with a horrendous, hard-to-diagnose ailment.
"It took a long time to figure out what it was." said medicalparasitologist Thomas Navin of the Centers for Disease Control andPrevention (CDC) in Atlanta. "For a while, they were considered ashaving Gulf War Syndrome," Navin told BioWorld Today, "butthose other people probably do not have visceral leishmaniasis,which these dozen patients, it turned out, did."
(Deputy Secretary of Defense John M. Deutch, wrote in yesterday'sNew York Times: [dated May 8]: "To date, we have been unable toidentify unambiguously what made these [Gulf War Syndrome]veterans sick.")
"Visceral leishmaniasis," Navin explained, "causes a typhoid-likeillness, which is usually fatal if untreated. The dozen," he hastened toadd, "all recovered."
Treatment, consisting of antimony-based compounds, is harsh butusually effective.
Leishmaniasis comes in two forms, visceral and cutaneous. The lattercauses chronic, leprosy-like skin ulcers, which are not fatal, but long-lasting unless treated. Both versions usually occur in tropical areas ofthe world, around the Mediterranean basin, extending to Iran andIraq.
The World Health Organization guesstimates that some 350 millionpeople around the world are at risk of acquiring leishmaniasis, withabout 12 million currently infected.
Just as the Anopheles mosquito alone transmits malaria, sandflieshave a monopoly on spreading leishmaniasis. "It's a misnomer tothink of sandflies occurring where it's sandy," Navin said. "Sandfliescan live in very dry areas, but not necessarily sandy ones. What youget bitten by at the beach are not generally sandflies."
Actually, two separate species of sandfly spread the leishmanialparasites globally. In the New World _ mainly Latin America _ theinsect's name is Lutzomyia; in the Old World, Phlebotomus.
"There are sandflies in the U.S.," Navin observed, "and there isleishmaniasis in the U.S. _ in southern Texas _ though it's not verycommon." He explained that "the reason there's not more is thatpeople in the U.S. really don't get bitten by as many insects as theydo in the tropics of Central America." He himself spent five yearsstudying leishmaniasis at a CDC parasitology research station inGuatemala.
Sandflies are the only vectors that transmit the infection, but domesticdogs are an important animal reservoir of leishmania.
Just as malarial parasites hole up and multiply in liver cells,leishmania force their way into mononuclear phagocytes. In thesemacrophages, they proliferate, swarm out, and spread toreticuloendothelial cells throughout the body.
Again like malaria, there is no effective immunization. "The WorldHealth Organization," Navin observed, "is funding efforts leading toPhase III large-scale field trials of a killed, whole-parasite vaccine.There is active research in the U.S.," he added, "to develop bettervaccine candidates. A number of groups are working on subunitvaccines "
A Leishmania Recombinant Antigen Passes Test In Mice
One such team is led by parasite immunologist Richard Locksley,chief of the infectious disease division at the University of California,San Francisco. His paper in last week's Science, dated April 28,bears the title: "Expression Cloning of a Protective LeishmaniaAntigen."
"Our research," Locksley told BioWorld Today, "suggested that therewas a single antigen, or peptide fragment of an antigen, that was seenearly by the immune system. We perceived that as important, becausea vaccine has got to target enough T lymphocytes that would berecruited at the time of natural infection."
He and his team cloned those parasite-specific T cells and used themto fish out this antigen. The clones interacted with a hybridoma thatcould present the expressed antigenic protein.
"We then completed the circle," Locksley added, "by taking therecombinant antigen, and proving that it could in fact protect miceagainst challenge by virulent Leishmania major [a cutaneous species],if given with the appropriate antigen, which in our case wasinterleukin-12." (See BioWorld Today, Jan. 18, 1995, p. 1.) Hispaper observed that "protection by a recombinant protein plus IL-12has not been demonstrated [heretofore]."
It concluded: "A similar strategy could be used with other infectiousdiseases in which protective CD4-dependent T cell responses havebeen described, thus paving the way for the development of newvaccines."
Locksley describes his Science article as being "simply a road map,where others might be interested in how to take a pathogen and find adominant antigen that might be of vaccine potential."
A "dominant antigen," he explained, "is one that served as the majorfocus of the T cell response."
Locksley vaccinated mice with the recombinant protein, rather thanwith naked DNA "in which people are now very interested as avaccine," he said. "If we study this protein very carefully," heobserved, "which the parasites present in the macrophages wherethey live, it may tell us the rules of antigen presentation in general."
He pointed out that "we've mapped the peptide, and know whichmoiety of amino acids are driving this whole response. We are nowvery interested in why it's those 14 amino acids, and not some otheramino acids."
On the way from mice to possible human trials, Locksley foreseesearly studies in dogs in France. His co-author Nicholas Gleichenhaus,is now employed there in Valbonne, at the Institute of Molecular andCellular Pharmacology. "Perhaps, too," Locksley said, "if things canbe lined up, we'd do studies in primates, as just a proof of principle."
He made the point, "We already know that humans who have hadleishmaniasis respond to this antigen, so it's also at least `seen' by theimmune system."
Locksley holds an issued patent on his leishmania antigen, andsuggests that "this is also a drug-target potential." But he thinks that"drug development for humans is a ways off. The track record for thepharmaceutical or biotechnology industry getting interested in adisease in developing countries is not super-high."
Immunologist Robert Seder, at the National Institute of Allergy andInfectious Diseases, mused, "If you knew the antigen to tuberculosisand the antigen to malaria, you could combine them [with this one ofLocksley's for leishmania] into one immunization. There wouldprobably be a commercial market for that, because the World HealthOrganization would say, `We're going to eliminate three majordiseases worldwide.'"
"What Locksley did," Seder remarked, "was find the area within thewhole gemish that is specific. It's probably a more elegant way to doa vaccine." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.