Potential cure for tropical parasitic disease found in soil
Common drug plus hormone provide one-two punch against deadly
Strongyloidiasis hyperinfection being reported in US

Date:
December 13, 2021
Source:
UT Southwestern Medical Center
Summary:
Combining two agents to block a parasitic worm's life cycle
boosted survival from a potentially deadly tropical disease to
85% in animal models, far better than either treatment alone,
according to a proof-of- concept study.



FULL STORY ========================================================================== Combining two agents to block a parasitic worm's life cycle boosted
survival from a potentially deadly tropical disease to 85% in
animal models, far better than either treatment alone, according
to a proof-of-concept study led by UT Southwestern Medical Center pharmacologists.


==========================================================================
The Strongyloides infestation -- brought by tiny worms known as
nematodes that can enter through your feet -- can cause strongyloidiasis,
a chronic infection found in some 600 million worldwide. While mostly
found in tropical and subtropical regions, the parasite has recently been identified in Texas, Alabama, and the Appalachian Mountains region in
the eastern and northeastern U.S. and caused reported deaths in 36 of 50
states over the years. Mortality from complications with hyperinfection
is up to 87% of reported cases, according to a 2020 modeling study.

"Parasitic nematodes that infect humans, animals, and plants are an
enormous health and economic burden on society. We think the pathway
we discovered could serve as a universal target for all parasitic
nematode species," said Howard Hughes Medical Center Investigator David Mangelsdorf, Ph.D., Chair of Pharmacology at UT Southwestern. "This
strategy could potentially offer a cure for the millions of people
around the world who have strongyloidiasis -- the disease caused by Strongyloides stercoralis- and points to a new way to fight many other parasitic nematode diseases." Researchers studying gerbils initially
found that administering dafachronic acid in drinking water for two weeks reduced fecal S. stercoralis larval output by 90%. In animals that became hyperinfected, which dramatically increases mortality, treatment with ivermectin or dafachronic acid alone increased survival to about 25%
and 70%, respectively. But when combined, survival climbed to about 85%
and S. stercoralis infection ended, representing a potential cure, said co-author Steven A. Kliewer, Ph.D., Professor of Molecular Biology and Pharmacology at UT Southwestern.

The two run the joint Mangelsdorf/Kliewer lab at UT Southwestern studying signal transduction pathways that offer new therapeutic potential for
treating diseases such as diabetes, obesity, cancer, and parasitism. The Mangelsdorf/ Kliewer lab discovered the existence of a nuclear receptor
pathway in parasitic nematodes and has shown that pharmacophores that
target this pathway may represent a new class of anthelmintic agents.

In this study published online in eLife, researchers targetedStrongyloides stercoralis, which can lead to a severe and potentially deadly
hyperinfection syndrome for people who are immunocompromised, such
as those taking glucocorticoids, a common steroid used to treat other
medical conditions.

"Glucocorticoids were one of the first treatments used for severe
COVID-19. WHO raised the concern that using steroids in countries
whereS. stercoralis is prevalent could set off a fatal hyperinfection in patients with chronic, subclinical strongyloidiasis. That possibility
has elevated the urgency for finding new ways to treat the disease,"
said Dr. Mangelsdorf, one of 25 members of the National Academy of
Sciences at UT Southwestern.

Drs. Mangelsdorf, Kliewer and colleagues looked for vulnerabilities in the larval stage of S. stercoralis' life cycle. By purifying extracts of S.

stercoralis, the team discovered that the parasite synthesizes
the hormone dafachronic acid, which acts by binding to a receptor
called DAF-12. Further research identified the enzymatic pathway that
S. stercoralis uses to generate the hormone and showed that the DAF-12
receptor acts as an on-off switch controlling larval development based
on the availability of dafachronic acid.

Importantly, when the hormone is present at the wrong time, the parasite
is unable to develop into the infectious form and dies.

Pure dafachronic acid in its present form may be unsuitable for treating
humans because of its short half-life in the body, said Dr. Kliewer,
also a member of the National Academy of Sciences. However, if chemistry techniques can be used to alter its structure, it could lead to a useful
drug. Because all parasitic nematodes have a similar stage in their
life cycles, he added, targeting this hormone and other points along
the dafachronic acid pathway could eventually be used to treat diseases
caused by other parasitic worms.

Work was funded by grants from the National Institutes of Health
(AI105856, GM141088, and AI050886), The Welch Foundation (I-1275,
I-1558, and I-2010- 20190330), UT Southwestern Eugene McDermott
Scholarship, and the Howard Hughes Medical Institute. Researchers
Zhu Wang, Mi Cheong Cheong, Jet Tsien, Heping Deng, and Tian Qin at
UT Southwestern also contributed to the study, along with researchers
from the Millersville University of Pennsylvania and the University of Pennsylvania, Philadelphia.

========================================================================== Story Source: Materials provided by UT_Southwestern_Medical_Center. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Zhu Wang, Mi Cheong Cheong, Jet Tsien, Heping Deng, Tian Qin,
Jonathan DC
Stoltzfus, Tegegn G Jaleta, Xinshe Li, James B Lok, Steven A
Kliewer, David J Mangelsdorf. Characterization of the endogenous
DAF-12 ligand and its use as an anthelmintic agent in Strongyloides
stercoralis. eLife, 2021; 10 DOI: 10.7554/eLife.73535 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/12/211213121907.htm

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