Researchers Find New Way to Study, Combat a Deadly Tropical Disease
Findings may help scientists develop treatments to help overcome this common parasitic infection
Infection with the parasitic roundworm Strongyloides stercoralis affects up to 100 million people worldwide. Although difficult to diagnose, once diagnosed, most S. stercoralis infections can be treated. However, some of those infected with this parasite will develop an aggressive hyperinfection in which the worms can overwhelm the patient. Treatment of patients with a hyperinfection is difficult and often not successful.
Researchers at Thomas Jefferson University, publishing in the journal Proceedings of the National Academy of Sciences (PNAS), have identified a new strategy that could be effective in attacking the parasite at its most aggressive stage and bring its numbers down to a point where it can be treated with available therapies.
“This is a neglected disease, not because it’s unimportant, but in part because it’s been difficult to diagnose and to study,” said senior author and infectious disease researcher David Abraham, PhD, a professor in the department of Microbiology and Immunology at the Sidney Kimmel Medical College of Thomas Jefferson University. “Our research helps explain how and when this species moves to the hyperinfection stage, provides a method for testing new treatments, and suggests a viable target for developing that treatment.”
Infection with S. stercoralis is known to flair into a hyperinfection in immune compromised patients or when the host is exposed to a steroid. For example, a glucocorticoid administered to suppress the immune system as treatment for another condition could trigger a hyperinfection in a patient whose S. stercoralis infection had gone undetected. During a hyperinfection, not only do parasite numbers in the gut increase, but increased numbers of parasites migrate outside of the gut and can cause organ failure. In addition, the gut bacteria that they spread can lead to complicating bacterial sepsis and contribute to a fatal outcome.
In order to study and better understand the development of S. stercoralis hyperinfections, the researchers identified a mouse strain that could be infected with S. stercoralis and that when treated with glucocorticoids would develop a hyperinfection much like that in humans. From their research findings using the new mouse model, Dr. Abraham and colleagues from the University of Pennsylvania and UT Southwestern found that a specific receptor called Ss-Daf-12 within the parasite may regulate the onset and/or maintenance of a hyperinfection. By modulating the receptor with an existing agent, the researchers significantly reduced development of hyperinfections in S. stercoralis infected mice treated with glucocorticoids.
They further confirmed that activation of the Ss-Daf-12 receptor reduced the worm burden in those glucocorticoid-treated infected mice. Of special interest was the reduction in the numbers of a specific larval form that can reinfect the host. In a typical infection, the first larval stage would pass out of the host and only develop into the infectious larval form outside of the host. During hyperinfections however, the first larval stage inside the host continues developing into an infectious larval form, resulting in a rapid increase in the host’s worm burden. Activation of the parasite’s Ss-Daf-12 receptor suppressed development of the infective larval form and prevented the development of hyperinfections in the mice.
Linking activation of the Ss-Daf-12 receptor in the parasite to both hyperinfection and development of an infective larval form inside the host may provide researchers with a drug development strategy to treat hyperinfection. In addition, the newly developed mouse model for S. stercoralis hyperinfection will provide a valuable means to test new treatment strategies. “It’s an approach that we think could be applied not just to this parasitic infection, but to many other species of parasites of both humans and animals,” says Dr. Abraham.
This work was supported by National Institutes of Health Grants AI105856 (to D.A., J.B.L., and D.J.M.), AI22662 (toJ.B.L.), OD P40-10939 (to Dr. Charles Vite), and R01DK067158 (to S.A.K. andD.J.M.); by Robert A. Welch Foundation Grants I-1558 (to S.A.K.) and I-1275 (to D.J.M.); and by the Howard Hughes Medical Institute (D.J.M.). The NIH Referral Center Grant OD P40-10939 (to Dr. Charles Vite) provided research materials for the study.
Article Reference: John B. Patton, Sandra Bonne-Année, Jessica Deckman, Jessica A. Hess, April Torigian, Thomas J. Nolan, Zhu Wang, Steven A. Kliewer, Amy C. Durham, James J. Lee, Mark L. Eberhard, David J. Mangelsdorf, James B. Lok, and David Abraham, “Methylprednisolone acetate induces, and Δ7-dafachronic acid suppresses, Strongyloides stercoralis hyperinfection in NSG mice,” Proc Natl Acad Sci U S A. 2018 Jan 2;115(1):204-209. doi: 10.1073/pnas.1712235114.