These overlooked global diseases take a turn under the microscope

The health post in Corte de Pedra, Bahia, Brazil, which treats about 1500 patients a year for the negelected tropical disease, cutaneous leishmaniasis.

Most people don’t die from tropical diseases like hookworm, schistosomiasis, or even malaria. But these understudied diseases, often caused by parasites, rob people of health in sometimes insidious ways.

For example, schistosomiasis is a disease caused by a waterborne, snail-transmitted parasite, and it’s the research focus of the School of Veterinary Medicine’s Robert Greenberg.

Schistosomiasis, a disease caused by parasitic flatworms, has long been a research focus for Penn Vet’s Robert Greenberg. (Image: John Donges/Penn Vet) “It’s not necessarily a death sentence, though there are fatalities” says Greenberg, a research associate professor of pathobiology. “But you get anemia, children get stunted in terms of growth and cognitive abilities. It’s a disease that keeps people in poverty.”

Such diseases, by and large, receive less financial support and, as a result, far less scientific attention than those that more often afflict residents of wealthier nations, such as diabetes and heart disease.

Penn Vet researchers, however, have committed attention to these diseases, which, taken as a whole, affect billions around the globe. Their work benefits from the niche strengths of the school, specifically in immunology and host-pathogen interactions.

“At the Vet School, a third of our funding supports infectious disease research,” says Phillip Scott, vice dean for research and academic resources and a professor of microbiology and immunology in the Department of Pathobiology. “That’s pretty amazing, given that the School is also awarded funding for regenerative medicine, for cancer, and for a variety of other areas.”

That strength is seen in the research portfolios of some of the more senior faculty, such as Christopher Hunter’s work on toxoplasmosis, James “Sparky” Lok’s studies of Strongyloides, Carolina Lopez’s investigations of lung infections, and Bruce Freedman and Ron Harty’s efforts against Ebola and other hemorrhagic viral diseases. It has attracted newer faculty members, like cryptosporidium expert Boris Striepen, to Penn Vet.

Parasitology professor James Lok’s studies of the development and basic biology of parasites, particularly the roundworm Strongyloides, have implications for finding new drug candidates. Veterinary schools have traditionally been strongholds of parasitology research, and Penn Vet is no exception. (Image: Eric Sucar)

Raising awareness Penn Vet’s De’Broski Herbert, for example, an associate professor of pathobiology, had held prior positions at Cincinnati Children’s Hospital and the University of California, San Francisco. He had felt called to work on hookworm, a parasite he first learned of growing up in the South from his great-grandmother, who warned him about walking around barefoot because of the risk of contracting the parasite. But at the medical centers where he worked, he shifted gears away from studying the parasite itself, instead focusing on related research in asthma and allergy.

As part of his hookworm research in Nigeria, Herbert (left), speaking with Babatunde Adewale of the Nigerian Institute for Medical Research, hopes to study the impacts of infection on the microbiome, the immune system, and more. (Image: Courtesy of De’Broski Herbert) “Here, our veterinary students are likely to encounter parasites in their patients, so working directly on the parasite is easier to justify,” Herbert says.

This spring, Herbert traveled to Nigeria where, working with partners at the Nigerian Institute for Medical Research, he launched a study of hookworm in 300 school-aged children in five sites around the northern and central portions of the country.

“The goal is to first establish what the prevalence of the disease really is and draw attention to that,” Herbert says. “And secondly, this is a place where the World Health Organization is going in and doing mass treatments, so I’m also interested in learning something very novel about the association between the microbiome, tissue repair, immune suppression, and metabolism in these children in Nigeria.”

Pairing basic and translational science Those insights could lead to treatments, but they will also likely shed new light on the basic science of how hookworms affect their host. This pairing of basic and applied work is characteristic of Penn Vet scientists. In Scott’s lab, for instance, which has long pursued studies of the tropical disease leishmaniasis, advances in basic science have unfurled alongside insights that stand to reshape treatment of this parasitic infection which, in its cutaneous form, can cause serious and chronic skin ulcers.

“When I was a postdoc at NIH, there’s something my boss used to say that I still use in my talks,” says Scott. “He said, ‘Leishmaniasis has done more for immunology than immunology has done for leishmaniasis.’ And you could substitute parasitology for leishmaniasis and it would be much the same quote.

The Leishmania parasite (in red), transmitted by a sandfly, can cause painful, disfiguring ulcers. Immunologist Phillip Scott and collaborators including Daniel Beiting have worked to understand the immune response to infection and better tailor treatment for those affected. (Image: Courtesy of Phillip Scott) “What I think is exciting right now,” he adds, “is that that’s going to change.”

As part of this contribution toward advancements against parasitic disease, Scott has traveled regularly to a leishmaniasis clinic in Brazil to obtain samples for his research and, back at Penn, has paired up with dermatology and microbiome experts such as Elizabeth Grice in the Perelman School of Medicine, and Dan Beiting from Penn Vet’s Center for Host-Microbial Interactions to break new ground.

No vaccine exists for leishmaniasis and current therapies fail a substantial percentage of the time. But recent publications from Scott’s lab have revealed new information about how the disease and existing treatments work and when to predict when they don’t. At the same time, Scott and colleagues’ research into the immunology of the infection has identified ways that FDA-approved drugs could be leveraged to alleviate the most severe forms of leishmaniasis.

New diagnostics A major hurdle to matching appropriate therapies with neglected disease comes at one of the earliest stages of medical intervention: diagnostics. Researchers at Penn Vet are employing innovative techniques to fill these unmet needs. Robert Greenberg is one who has crossed disciplinary boundaries to do so.

In a partnership between Greenberg and Haim Bau of Penn’s School of Engineering and Applied Science, the scientists are working to craft an improved diagnostic test for schistosomes, which can lead to schistosomiasis, causing anemia, tissue fibrosis and lesions, malnutrition, learning difficulties, and, depending on the parasite species, bladder cancer and heightened HIV risk.

Greenberg has studied the ion channels that govern key biological functions in schistosomes to potentially develop drug targets that paralyze and kill the organisms. And by adapting insights from other researchers about additional parasitic-specific targets, he’s helping Bau train his microfluidic, portable diagnostic system on schistosomes to one day help clinicians make point-of-care diagnoses and issue timely treatment for infected patients.

“The current diagnostics are pretty terrible,” Greenberg says. “We’re looking at some new approaches now that should give us a much earlier, more sensitive, and more specific diagnosis for individual patients that might be able to detect other coinfections simultaneously.”

At Penn Vet’s New Bolton Center, Marie-Eve Fecteau and Ray Sweeney are also taking part in the design of a 21st-century solution to diagnostics of an insidious and challenging disease, in this case, a disease that takes a particular toll on livestock: paratuberculosis, or Johne’s disease. Caused by the bacterium Mycobacterium avium paratuberculosis, the condition affects ruminants such as cows and goats and drastically decreases their weight and milk production.

Infectious diseases take a toll on livestock as well, indirectly impacting human health and livelihoods. Large animal veterinarians Marie-Eve Fecteau and Raymond Sweeney are making progress on a stall-side diagnostic system that could quickly identify calves infected with paratuberculosis, halting the spread of infection. (Image: Louisa Shepard) “Ruminants are a very important part of survival and livelihood in developing countries,” says Fecteau, an associate professor of food animal medicine and surgery. “Families may rely on only one or two cows to provide for their nutritional needs or income, and if that cow is affected by Johne’s, that’s a serious problem.”

Paratuberculosis has been shown to be endemic in parts of India and elsewhere in Asia and is also a burden for U.S. farms, where 70% of dairy herds test positive for the infection. Separating infected animals from the herd is a key step to stem the spread, but the bacteria have proved difficult to grow in the lab, making diagnosis challenging.

Fecteau and Sweeney, the Mark Whittier & Lila Griswold Allam Professor at Penn Vet, are hoping to change that, working with Beiting and biotechnology firm Biomeme to develop a “lab in a fanny pack,” as they call it: A stall-side diagnostic test that relies on PCR to identify infected animals from stool samples within hours.

“This is the kind of technology that could be extremely valuable for use in areas where sophisticated technology is harder to come by,” says Sweeney.

Stopping disease where it starts Elsewhere at Penn Vet, researchers are approaching globally significant diseases by focusing on the vector. In the insectary that is part of Michael Povelones’s lab, he and his team test methods to stop disease-transmission cycles within mosquitoes.

In the work, which relies on disrupting the way that mosquitoes interact with or respond immunologically to the pathogens they pass on, Povelones, an assistant professor of pathobiology, has explored everything from dengue to Zika to heart worm to elephantiasis, and his discoveries have implications for targeting a much longer list of diseases. In a recent study, Povelones and colleagues developed a new model system for studying the transmission of diseases caused by kinetoplastids, a group of parasites that includes the causative agents of Chagas disease and leishmaniasis.

“We think this could be a model for a number of important neglected diseases,” Povelones says.

In the latest of his team’s work finding ways to activate mosquitoes’ immune system to prevent pathogen transmission, they’ve identified a strategy that both blocks heartworm and the parasite that causes elephantiasis.

“These two diseases have very different behavior once they’re in the mosquito, so we’re still figuring out why this seems to work for both,” says Povelones. “But we’re very encouraged that it does.”

Using these types of creative approaches is a common thread across the Vet School, and the researchers’ efforts and successes seem to be multiplying. To continue accelerating progress, the School is developing a plan to harness these strengths, working with existing entities such as the Center for Host-Microbial Interactions internally and cross-school units such as the Institute for Immunology.

“We are a key part of the biomedical community at Penn and bring a valuable veterinary component to the table in confronting diseases of poverty,” says Scott.


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