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VA researchers are helping to build a new understanding of infectious diseases that are common in areas where U.S. troops are deployed

Given the threats they face each day, U.S. troops abroad likely don’t worry much about bug bites. Two diseases—leishmaniasis and malaria—can infect them through insect bites, and both diseases carry the potential for serious consequences. Another infectious disease common in areas of the world where U.S. troops are deployed, tuberculosis, is spread directly from human to human. With no effective vaccines available yet for any of these diseases, Department of Veterans Affairs (VA) researchers are among those seeking better ways to prevent, diagnose, and treat the illnesses. Part of the work involves studying the human immune system’s reaction to these invisible dangers.

Sand fly bites: More than a nuisance

Immunity booster—Dr. Laurence Buxbaum, an infectious-disease specialist at the Philadelphia VA Medical Center and University of Pennsylvania, is studying how to bolster the body’s immune response to the parasite that causes leishmaniasis. Photo by Tommy Leonardi.

Worldwide, about 350 million people are at risk for leishmaniasis, which has multiple forms. All are caused by one-celled parasites of the Leishmania species that are spread by sand fly bites.

In recent years U.S. troops have sustained only a handful of cases of visceral leishmaniasis—the most serious form of the disease, which is usually fatal without treatment. A far more common, and milder, form of the disease is cutaneous leishmaniasis, which produces sores around the bite. Some patients develop only an insignificant sore that disappears on its own. Others develop deeper sores. Without treatment, the sores usually disappear over time, although they can last for months and form scars, or become chronic, non-healing lesions.

Cutaneous leishmaniasis is rare in the U.S. Cases have been found in Texas, near the border with Mexico, but it is much more common in the Middle East. Afghanistan’s capital, Kabul, is a high-risk site for leishmaniasis. According to the World Health Organization, about 200,000 cases occur there each year. A 2003 study found that about three percent of Kabul residents had active leishmaniasis, and another 22 percent had scarring from past infections.

Since 2003, there have been about 3,000 documented cases of leishmaniasis, almost all of which were the cutaneous form, according to Col. Alan Magill, M.D., former division director of experimental therapeutics at the Walter Reed Army Institute of Research (WRAIR) and attending physician with the infectious disease service at Walter Reed Army Medical Center.

In 2003 and 2004, nearly 1,400 U.S. personnel in Iraq and Afghanistan were diagnosed with cutaneous leishmaniasis, in the largest recorded outbreak of the disease. Magill said that cases now stand at about 100 per year. “Protective clothing, DEET (an Army-developed chemical that today is used in most insect repellents), bed nets, they all work well as prevention,” he said. “The vast majority of cases occurred in the first year or so, when many people were sleeping out in the desert. Now it’s a more mature environment, and cases have dropped dramatically.”

However, Magill estimates that for every diagnosed case of leishmaniasis, three to five others are never seen because the lesions aren’t serious enough for soldiers to seek medical treatment or they do not want to leave their units.

Laurence Buxbaum, M.D., Ph.D., a physician-scientist at the Philadelphia VA Medical Center and University of Pennsylvania, studies the body’s immune response to the Leishmania parasite. In general, there are two types of immunity: innate immunity, a general response by the body that’s required to fight off pathogens; and adaptive immunity, a specific response in which the body creates antibodies and mounts cell-mediated responses against an invader.

Buxbaum has discovered that the antibodies created by the adaptive immune system in response to the parasite might be doing more harm than good. They induce the body to make a protein called interleukin-10 (IL-10), which in turn suppresses the cell-mediated phase of the adaptive immune response.

“IL-10 normally prevents an immune response to infection from getting out of hand,” Buxbaum said. “But in leishmaniasis, you don’t want that to happen; the immune system response is dampened when you actually want it strengthened.”

He’s now studying what part of the parasite attracts the antibodies. If he can pinpoint that part, “We could block the antibody response by creating a drug that looks like the target. The antibody would bind to the drug instead of the parasite, no IL-10 would be produced and your body could fight off the parasite more strongly.”

A vaccine for this disease is not an immediate possibility, he said. “Vaccines work by using protective antibodies, and in leishmaniasis it’s likely that any antibody response you’d get would make things worse.”

Mary Wilson, M.D., of the Iowa City VA Medical Center and the University of Iowa, studies the genetics of outcomes to leishmaniasis infection. She and her colleagues have collected information on more than 1,400 people who live where leishmaniasis is endemic. They hope to determine whether certain genes are associated with risk of infection, and whether others are linked with better or worse outcomes after infection. Wilson’s research could lead to gene-based treatment or prevention strategies.

Malaria: Common to Afghanistan’s river valleys

Each year, malaria strikes about 250 million people worldwide, killing one million. Like leishmaniasis, there are multiple types of malaria, all of which result from infection by Plasmodium parasites, carried from person to person by mosquitoes.

While there is no malaria in Iraq, both P. vivax and P. falciparum forms have infected soldiers in Afghanistan, said Magill. “It’s seasonal there, and not urban. But there is malaria in the river valleys.”

Soldiers are prescribed a daily preventive pill for malaria. “If they take it daily, they’re unlikely to get malaria,” according to Magill. “But like anything you have to do every day, it doesn’t always happen.” In addition to taking the pill, troops are advised to use DEET products and cover their skin to ward off mosquito bites in the first place.

Magill recalls only a few severe, complicated cases of malaria since 2003, with soldiers being treated in Germany or at Walter Reed Army Medical Center. He’s also seen cases of P. vivax malaria in veterans who have been back in the U.S. for weeks or months. The P. vivax parasite can lie dormant in the liver for months and then cause a relapse, making it complex to diagnose.

“We’ve had relapsed vivax cases in which someone shows up with a bad fever, a headache,” he said. Under those conditions, “we assume that if they were in Afghanistan within the year, they have malaria until proven otherwise.” But most hospitals in the U.S. are not going to diagnose malaria, he stated, because it’s not on the radar: Basically, the disease doesn’t exist here.

Battling drug-resistant malaria

Malaria maven—Dr. Michael Riscoe, with the Portland VA Medical Center and Oregon Health and Science University, is working on new drugs to combat malaria. The disease, spread by mosquitoes, kills a million people worldwide each year and poses a threat to U.S. troops who are unable to keep up with preventive steps such as taking a daily doxycycline pill. Photo by Michael Moody.

Drug treatment options for malaria are few; all strains of the disease are now resistant to quinine and chloroquine, which used to be standard treatments. Michael Riscoe, Ph.D., at the Portland VA Medical Center has several projects underway to find new drugs.

Supported by the VA, the National Institutes of Health and the Medicines for Malaria Venture, Riscoe’s team and colleagues at the University of South Florida are designing and testing drugs that will block the function of parasite mitochondria while leaving human cells untouched. Mitochondria are the energy-creation centers of cells; without them, cells die. The potential drugs, in a class called quinolones, could be tested in humans within the next two to three years, Riscoe said.

He is also working on synthesizing a “chemical cousin” of chloroquine that works without the problem of drug resistance. According to Riscoe, that drug, about which he is very optimistic, is three or four years away from clinical testing.

One roadblock to discovering malaria drugs is that the parasite takes on several forms. After infection by a mosquito, the parasite hides in the liver, replicating for a week or two. Then a different form is released into the bloodstream, causing a high, spiking fever. The bloodstream form invades red blood cells and replicates there. A third form can be picked up by a feeding mosquito and transmitted to another person.

The chloroquine-like drug that Riscoe envisions would work against the bloodstream parasites, but not the other two forms. The quinolone drugs—which block parasite mitochondria—appear active against all three forms of the parasite. “The great hope,” said Riscoe, “is that we could use these drugs to both treat and prevent malaria.”

Tuberculosis Vaccine in the Works

Field test—Dr. Suman Laal, with the VA and New York University, is developing a rapid, point-of-care test for tuberculosis that can be used in war zones and other settings. Photo by Lamel Hinton.

Tuberculosis (TB) is endemic in both the Middle East and Afghanistan, putting U.S. soldiers at risk for infection, according to Suman Laal, Ph.D., a research career scientist with the VA and an associate professor of pathology and microbiology at New York University.

The bacterium that causes the infection—Mycobacterium tuberculosis—usually attacks the lung and is spread through coughing. When a TB patient coughs, droplets carrying bacteria are released into the environment. Any person who breathes in these droplets can get infected. Treatment involves multiple drugs and lasts at least six months.

M. tuberculosis grows slowly, so it can be months or years between infection and symptoms developing. So military personnel infected in Afghanistan or Iraq may develop TB several months or years after returning stateside. There is no effective prevention for TB, and there are no simple tests to diagnose it in the field. Moreover, said Laal, the tests that are available work only after symptoms are present, not before.

Laal’s research focuses on developing a rapid, point-of-care test for this disease. Her group has found several candidate antigens—bacterial proteins—that could be used in such a test. They also have identified antigens that appear to play roles in the initial infection by the bacteria. These antigens could be used to design a TB vaccine to prevent infection altogether, she said.