TY - JOUR
T1 - Methylprednisolone acetate induces, and ?7-dafachronic acid suppresses, Strongyloides stercoralis hyperinfection in NSG mice
AU - Patton, John B.
AU - Bonne-Année, Sandra
AU - Deckman, Jessica
AU - Hess, Jessica A.
AU - Torigian, April
AU - Nolan, Thomas J.
AU - Wang, Zhu
AU - Kliewer, Steven A.
AU - Durham, Amy C.
AU - Lee, James J.
AU - Eberhard, Mark L.
AU - Mangelsdorf, David J.
AU - Lok, James B.
AU - Abraham, David
N1 - Funding Information:
ACKNOWLEDGMENTS. We thank Hongguang Shao, Grace Zhang, Nicole Bacarella, Erika Klemp, and Lindsay McMenemy for technical assistance. We thank Noelle Williams and the University of Texas Southwestern Preclinical Pharmacology Core for determining the pharmacokinetics of Δ7-DA. We thank Tim Manser for identifying the initial resources and for providing encouragement for these studies. This work was supported by National Institutes of Health Grants AI105856 (to D.A., J.B.L., and D.J.M.), AI22662 (to J.B.L.), OD P40-10939 (to Dr. Charles Vite), and R01DK067158 (to S.A.K. and D.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.
PY - 2018/1/2
Y1 - 2018/1/2
N2 - Strongyloides stercoralis hyperinfection causes high mortality rates in humans, and, while hyperinfection can be induced by immunosuppressive glucocorticoids, the pathogenesis remains unknown. Since immunocompetent mice are resistant to infection with S. stercoralis, we hypothesized that NSG mice, which have a reduced innate immune response and lack adaptive immunity, would be susceptible to the infection and develop hyperinfection. Interestingly, despite the presence of large numbers of adult and first-stage larvae in S. stercoralis-infected NSG mice, no hyperinfection was observed even when the mice were treated with a monoclonal antibody to eliminate residual granulocyte activity. NSG mice were then infected with third-stage larvae and treated for 6 wk with methylprednisolone acetate (MPA), a synthetic glucocorticoid. MPA treatment of infected mice resulted in 50% mortality and caused a significant >10-fold increase in the number of parasitic female worms compared with infected untreated mice. In addition, autoinfective third-stage larvae, which initiate hyperinfection, were found in high numbers in MPA-treated, but not untreated, mice. Remarkably, treatment with ?7-dafachronic acid, an agonist of the parasite nuclear receptor Ss-DAF-12, significantly reduced the worm burden in MPA-treated mice undergoing hyperinfection with S. stercoralis. Overall, this study provides a useful mouse model for S. stercoralis autoinfection and suggests a therapeutic strategy for treating lethal hyperinfection.
AB - Strongyloides stercoralis hyperinfection causes high mortality rates in humans, and, while hyperinfection can be induced by immunosuppressive glucocorticoids, the pathogenesis remains unknown. Since immunocompetent mice are resistant to infection with S. stercoralis, we hypothesized that NSG mice, which have a reduced innate immune response and lack adaptive immunity, would be susceptible to the infection and develop hyperinfection. Interestingly, despite the presence of large numbers of adult and first-stage larvae in S. stercoralis-infected NSG mice, no hyperinfection was observed even when the mice were treated with a monoclonal antibody to eliminate residual granulocyte activity. NSG mice were then infected with third-stage larvae and treated for 6 wk with methylprednisolone acetate (MPA), a synthetic glucocorticoid. MPA treatment of infected mice resulted in 50% mortality and caused a significant >10-fold increase in the number of parasitic female worms compared with infected untreated mice. In addition, autoinfective third-stage larvae, which initiate hyperinfection, were found in high numbers in MPA-treated, but not untreated, mice. Remarkably, treatment with ?7-dafachronic acid, an agonist of the parasite nuclear receptor Ss-DAF-12, significantly reduced the worm burden in MPA-treated mice undergoing hyperinfection with S. stercoralis. Overall, this study provides a useful mouse model for S. stercoralis autoinfection and suggests a therapeutic strategy for treating lethal hyperinfection.
KW - Dafachronic acid
KW - Glucocorticoid
KW - Hyperinfection
KW - NSG mice
KW - Strongyloides stercoralis
UR - http://www.scopus.com/inward/record.url?scp=85040161208&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85040161208&partnerID=8YFLogxK
U2 - 10.1073/pnas.1712235114
DO - 10.1073/pnas.1712235114
M3 - Article
C2 - 29203662
AN - SCOPUS:85040161208
SN - 0027-8424
VL - 115
SP - 204
EP - 209
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 1
ER -