Global campaigns to eliminate two tropical parasitic worm infections have been hindered by a lack of good diagnostic tools. Since the turn of the century, multinational mass drug-treatment efforts have cut the number of people at risk of lymphatic filariasis and onchocerciasis by more than half, but more than half a billion people remain at risk. The next phases of these global disease elimination programs will require better tests for detecting people who are infected and infectious for others.
Researchers at Washington University School of Medicine in St. Louis have received a $2.95 million grant from the Bill & Melinda Gates Foundation to create improved diagnostics for the two worm infections. The object in both cases is to find a marker in the blood that indicates when a person is capable of passing the infection to others. The project is led by principal investigator Peter Fischer, PhD, a professor of medicine.
“We want it to be as easy as a pregnancy test,” said co-investigator Gary Weil, MD, a professor of medicine and of molecular microbiology. “Just a drop of blood and you know whether someone is infected or not in a matter of minutes.”
Both infections are spread by biting insects: blackflies for onchocerciasis — also known as river blindness — and mosquitoes for lymphatic filariasis, which also is called elephantiasis because sufferers can develop hugely swollen legs. Worm larvae in the blood of infected people are ingested by the insect when it takes a blood meal, and later passed to another person. Once inside a person’s body, the larvae mature into adults, mate and begin producing young that migrate to the blood, ready to be picked up by the next biting insect. Adult worms can survive in humans and release larvae for years. Mass drug campaigns aim to break the cycle of transmission by treating whole communities annually to cure infections and prevent new ones.
Weil leads and Fischer co-leads the university’s long-running Death to Onchocerciasis and Lymphatic Filariasis (DOLF) program — also supported by the Gates Foundation — that supports global efforts to eliminate both diseases. Among other accomplishments, DOLF’s research has led to improvements in the multidrug treatment regimen for lymphatic filariasis.
For onchocerciasis, the problem is that the drugs kill the larvae but mostly spare the adults. So a round of drug treatment may not break the cycle of transmission so much as pause it until the surviving adult worms start producing more young.
Adult onchocerciasis worms cocoon themselves in small marble-sized nodules under the skin. The only way to tell whether someone harbors live adult worms is to cut out the nodule and inspect the worms under a microscope.
“It is not as easy as you might think to tell whether a worm is alive or dead,” Fischer said. “They undergo morphological changes as they age, and it can be difficult to tell the difference visually between an old but viable worm and a worm that has been damaged by drug treatment.”
The process is laborious and cannot easily be scaled up. Moreover, people are not always eager to participate in nodule surgery. Without a good way to determine how many people retain live adult worms, public health officials struggle to decide when a cycle of transmission has been broken so that expensive and logistically complex mass treatment programs can be halted.
For lymphatic filariasis, the problem is a bit different. To determine whether a person is infectious, scientists look for larvae in his or her blood. But the larvae of lymphatic filariasis worms can’t be found in the bloodstream during the day, when people are available to give blood samples. The larvae swarm from the lungs into the blood only at night, when mosquitoes bite. What is needed, therefore, is a blood biomarker for the presence of larvae that can be detected with blood collected during the day or night.
To find blood biomarkers for the two diseases, Fischer and colleagues are analyzing blood samples collected from people in Cote d’Ivoire, Ghana, Indonesia, Liberia and Papua New Guinea. The researchers will first screen the blood samples to identify worm molecules present in the blood of people who harbor live adult worms (for onchocerciasis) or larvae (for lymphatic filariasis). Once they have identified potential biomarkers, the researchers will generate antibodies to the biomarkers that will be used to develop easy-to-use diagnostic tests similar to pregnancy tests.
“It’s like looking for a needle in a haystack, where the haystack is the blood and the needle is that one tiny drop of worm juice,” Weil said. “Big science requires big teamwork. Our team includes proteomics experts whose job it is to find that needle. Then the genomics and bioinformatics experts tell us whether what we’ve found is truly unique, or whether it also can be detected in healthy people or people with other kinds of worm infections. Our group has collected the blood samples needed for this work over many years, and we know how to make the antibodies and design and evaluate new tests.”
The research team includes co-investigators Makedonka Mitreva, PhD, a professor of medicine and of genetics, Bruce A. Rosa, PhD, an assistant professor of medicine in infectious diseases, Philip J. Budge, MD, PhD, an assistant professor of medicine in infectious diseases, and Reid Townsend, MD, PhD, a professor of medicine who directs the School of Medicine’s Proteomics Core Laboratory.
“The COVID pandemic has made it very apparent to everyone how important good diagnostic tests are for controlling infectious diseases,” Fischer said. “Worldwide, enormous progress has been made in reducing the number of people at risk for both of these diseases, but once we have better diagnostic tests, we will be much better positioned to finish the job of eliminating these parasites as public health threats.”