Disease follows war like a pack of hungry dogs, feeding when opportunities arise and killing when defenses are down. Refugees, displaced and malnourished by the chaos, typically suffer first and most. But soldiers, when not dodging bullets or explosives, may fall victim as well, particularly if dropped into foreign climate zones where swarms of native bugs are only too happy to feast on exposed skin and new blood.

Such has been the unhappy fate of more than 650 American soldiers in Afghanistan and Iraq -- 9 of them women -- diagnosed with a parasitic disease called leishmaniasis. Transmitted by the bite of local sand flies, leishmaniasis comes in several major forms, each with its own disfiguring or deadly characteristics. (See "Terrible Toll") Cutaneous leishmaniasis, by far the most common form of the million or so cases reported around the world each year, causes weeping, crater-like sores on areas of exposed skin -- such as the neck, arms and face -- where flies inject the parasites. The unsightly craters are not infectious and eventually heal on their own, but even with treatment, the process may take months or years and can leave burnlike scars. A second major form, known as visceral leishmaniasis, concentrates its attack on the body's internal organs. If left untreated, it is uniformly fatal.

So far, most of the American soldiers diagnosed with leishmaniasis have developed the skin form of the disease, which has an incubation period of two to six months. All, even the handful with visceral leishmaniasis, have been "successfully treated," reports Col. Dallas Hack, chief of preventive medicine at Walter Reed Army Medical Center. The treatment of choice is a 60-year-old investigational drug called Pentostam, first developed for American troops during World War II. Pentostam carries its own risks; side effects include liver, pancreas and heart damage, one reason why stricken soldiers are returned to one of three military medical sites in the US, evaluated and, if treatment is required, carefully monitored as outpatients during the 10- to 20-day regimen. Newer, less toxic treatments, particularly a laser wand that burns the lesions and speeds healing, are now being tested as well. Yet, when it comes to leishmaniasis, successful treatment does not necessarily mean a cure. True, infection with cutaneous leishmaniasis imparts a lifetime immunity. But it does not protect against the threat of visceral leishmaniasis should a victim's immune system suffer some insult later in life.

Already, published reports from Africa and areas around the Mediterranean tell disturbing stories of AIDS patients whose old -- and formerly quiescent cases of cutaneous leishmaniasis -- have morphed into the visceral form as their immune systems have degraded. The rise of this opportunistic infection comes as no surprise to UCSF immunologist Richard Locksley, whose research into the adaptive immune response (see "Breaking Down the Immune System") -- particularly some key players known as T cells -- has pivoted around his mouse model of the visceral form of the disease. Since the research began more than a decade ago, Locksley and his colleagues have uncovered the series of cellular events that define how a healthy immune system mobilizes against the parasitic Leishmania, and when compromised, how it fails. Locksley's team also has found a Leishmania antigen that, when shut down via genetic methods, strips the parasites of their ability to reproduce.

This antigen is just one of several drug targets emerging at UCSF. At the Sandler Center for Basic Research in Parasitic Diseases, and his colleagues are focusing their efforts on turning off enzymes that are essential to the ability of the Leishmania to grow and divide in host cells. McKerrow is cautious -- "Mouse models do not necessarily predict what will happen in human patients" -- but encouraged. It is easy to see why. Knocking out the genes responsible for producing parasite proteases has produced dramatic effects: Mice were lesion free and had fewer parasites overall. Better yet, McKerrow has found some potential inhibitors that lock up the binding sites of these proteases in a selective fashion, thereby minimizing potential side effects.

"We used the same structure-based drug design strategies we used when targeting Leishmania's "cousin" the Chagas' disease parasite (a cardiac disease common in Latin America). Our work trying to shut down the Chagas' parasite helped us find something similar in the Leishmania donovani parasite," McKerrow explains. Work now continues on the several drug targets that seem the strongest contenders. And if plans for developing a phase 1 testing capacity of new drugs within UCSF come to pass (phase 1 clinical trials evaluate new drugs for safety and efficacy), the University could ultimately hold the hopes of millions in its hands. (See "Terrible Toll" and "Old Drugs for an Old Disease.") "The ideal protection would be a vaccine," says McKerrow, "but even if we are successful, that is years away." Similarly, while a boon to those at risk for contracting leishmaniasis in the future, a vaccine will be of no help to those already infected, including the growing number of American military personnel; they will need to be on guard against the signs of visceral leishmaniasis for years to come. Adds Hack, "Civilian doctors are not used to having visceral leishmaniasis on their radar, but with so many reservists having seen duty [in Iraq and Afghanistan], they will now have to consider it a possibility if someone shows up with generalized fever and abdominal pain." The health, and perhaps the lives, of many will depend on it.

In Harm's Way - Page 2