Fly by Night

Tiny, blood-sucking sand flies are responsible for transmitting the 20 or so infective species of the Leishmania parasite. The flies, which have a life cycle of just 20 to 40 days, feed on small mammals infected with the disease, usually rodents or domesticated animals like dogs, and then inject the parasite into human hosts. Most active from dusk to dawn, the flies -- only one-third the size of mosquitoes -- are notoriously difficult to eradicate or control, although insecticides can significantly reduce their numbers. In some areas of Iraq, where, early in the war, soldiers were sleeping unprotected in or around their vehicles, the percentage of sand flies later found to be infected was as high as 2 percent. The expected rate of infection was one-tenth of 1 percent.

Terrible Toll

In addition to cutaneous and visceral leishmaniasis, there are two other major forms of the disease. Mucocutaneous leishmaniasis, caused by the infection of a Brazilian form of the parasite, begins with skin ulcers that ultimately heal. After an asymptomatic period that can last as long as a decade, the lesions reappear and quickly destroy all the tissue of the nose and mouth. Diffuse cutaneous leishmaniasis produces widespread and persistent lesions and nodes that can be mistaken for leprosy. Both forms resist standard treatments.

Endemic in 88 countries on four continents, leishmaniasis incidence is about 2 million cases annually, one-quarter of which are of the visceral variety. More than 90 percent of cutaneous leishmaniasis cases occur in Iran, Afghanistan, Nepal, Syria, Saudi Arabia, Brazil and Peru. More than 90 percent of visceral leishmaniasis cases occur in Bangladesh, Brazil, India and Sudan. An estimated 200,000 die from the disease each year.

The View from Uberlandia

Silvio Favoreto, a scientist at UCSF's Cardiovascular Research Institute, hails from a city in south-central Brazil called Uberlandia. Lately, this fictional-sounding metropolis has been confronted with a very real problem, an outbreak of leishmaniasis, triggered by environmental disruption.

Known for its nearby coffee plantations, cattle grazing and chemical industries, Uberlandia has doubled in size in the last decade, pushing the city's population into closer contact with wildlife. In addition, the construction of five new dams within 100 miles of the city has ravaged the natural vegetation and driven wild mammals into more inhabited areas. The collision of infected animals with human populations has produced a predictable spike in leishmaniasis cases, says Favoreto, who, in partnership with the San Francisco-based Sustainable Sciences Institute, helps to train young Brazilian scientists in the most advanced diagnostic techniques.

Favoreto and his colleagues do not have to look far for a patient population. Indeed, in one farming cooperative of approximately 600 people near the laboratory, one-quarter of the farmers are infected. Sadly, many of the Uberlandia patients develop the mucocutaneous form of the disease and suffer its accompanying disfigurement. (See "Terrible Toll.") The migration of a neighboring Leishmania parasite from the Amazon region is causing further alarm. "We are tracking the migration closely because this parasite is known to cause the diffuse form of leishmaniasis, which presents even higher morbidity," Favoreto explains.

Favoreto's goal is to reduce the leishmaniasis diagnoses from weeks to hours by using highly sensitive and specific techniques that distinguish this disease from the Chagas' disease cases that also prevail in the region (both diseases cross-react to conventional diagnostic tests). "We are trying to prevent an emerging disease from becoming seriously endemic," says the Brazilian native. The urgency is real. From a handful of cases each year, the number has now risen to 500 and continues to grow.

Favoreto knows that he and his colleagues are working against tough odds and that current drug treatments have a spotty record of success. "The one sure thing is that once you're infected, these bugs are going to be part of your life for a long time."

Old Drugs for an Old Disease

Leishmaniasis is named for Scottish physician William Leishman, who first diagnosed the cause of the disease while serving with the British army in India in the early 1900s. It is fitting then that contemporary India, where most of the world's visceral cases of the disease are found and where parasite resistance to existing treatments is growing, is now home to two promising clinical trials of anti-visceral leishmaniasis drugs. One, being conducted by the Indian Council of Medical Research in collaboration with the World Health Organization's Tropical Disease Research Programme (TDR), studies oral miltefosine, an established cancer drug that when used in small doses, seems to cure what is locally called kala-azar with minimal side effects. Another trial, held under the auspices of the San Francisco-based Institute for OneWorld Health, a nonprofit pharmaceutical company founded by UCSF School of Pharmacy graduate Victoria Hale, tests paromomycin, a wide-spectrum antibiotic. Phase 3 testing of the drug (being conducted in collaboration with the TDR and funded by the Bill and Melinda Gates Foundation) shows that it, too, can cure kala-azar. Given that visceral leishmaniasis is a disease that usually afflicts the poorest of the poor, the new treatments are being fashioned as cheap and simple to administer. Better yet, once cured of kala-azar, patients have lifelong immunity against the disease.

Breaking Down the Immune System

Remember Me? The Adaptive Immune Response

An immune response that is specifically directed at particular antigens on a disease pathogen. Certain lymphocyte cells of the adaptive immune response retain a memory of prior exposure to antigens on pathogens, including antigens in vaccines. This permits a stronger immune response if the same pathogen is encountered again.

Born Killers: The Innate Immune Response

An early and relatively nonspecific response to infection coordinated by certain cell types, such as neutrophils, macrophages and natural killer cells, and their associated cytokines.

Hooking Up: Antigen

A molecule on an invading pathogen that stimulates an immune response.

Smart Cells: Lymphocytes

Adaptive immune system cells. Lymphocytes include B and T lymphocytes, which target specific antigens and which are also responsible for immunologic memory.

Lock and Fire: Antigen Receptor

A specialized protein that populates the surface of a T or B lymphocyte. It signals a pathogen invasion when it binds to the target antigen, which in turn causes the production of more lymphocytes that inactivate or destroy the bacteria, viruses, fungi or parasites that are causing the infection.

Can You Hear Me Now? Cytokine

A type of protein produced by many different cell types that mediates inflammatory and immune reactions. Cytokines are the principal mediators of communication between the cells of the immune system.

In Harm's Way - Page 1