Published March 1, 2022 | Supplemental Material + Published
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Nematode ascarosides attenuate mammalian type 2 inflammatory responses

Abstract

Mounting evidence suggests that nematode infection can protect against disorders of immune dysregulation. Administration of live parasites or their excretory/secretory (ES) products has shown therapeutic effects across a wide range of animal models for immune disorders, including asthma. Human clinical trials of live parasite ingestion for the treatment of immune disorders have produced promising results, yet concerns persist regarding the ingestion of pathogenic organisms and the immunogenicity of protein components. Despite extensive efforts to define the active components of ES products, no small molecules with immune regulatory activity have been identified from nematodes. Here we show that an evolutionarily conserved family of nematode pheromones called ascarosides strongly modulates the pulmonary immune response and reduces asthma severity in mice. Screening the inhibitory effects of ascarosides produced by animal-parasitic nematodes on the development of asthma in an ovalbumin (OVA) murine model, we found that administration of nanogram quantities of ascr#7 prevented the development of lung eosinophilia, goblet cell metaplasia, and airway hyperreactivity. Ascr#7 suppressed the production of IL-33 from lung epithelial cells and reduced the number of memory-type pathogenic Th2 cells and ILC2s in the lung, both key drivers of the pathology of asthma. Our findings suggest that the mammalian immune system recognizes ascarosides as an evolutionarily conserved molecular signature of parasitic nematodes. The identification of a nematode-produced small molecule underlying the well-documented immunomodulatory effects of ES products may enable the development of treatment strategies for allergic diseases.

Additional Information

© 2022 the Author(s). Published by PNAS. This article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND). Contributed by Paul W. Sternberg; received May 13, 2021; accepted December 28, 2021; reviewed by Rick Maizels and Steven Ziegler. We thank Ellen Rothenberg, Mary Yui, and Sylvia Vetrone for their invaluable discussions and advice. We thank Ed Platzer for his assistance with the smES preparation and Stephan H. von Reuss and Sydney Campbell for analyzing nematode extracts. We also thank Kaoru Sugaya and Toshihiro Ito for their excellent technical assistance. This work was supported by the Ministry of Education, Culture, Sports, Science and Technology (MEXT Japan) Grants-in-Aid for Scientific Research (S) JP19H05650, (B) 20H03685, (C) 17K08876, 18K07164, and 19K16683, Transformative Research Areas (B) JP21H05120, and JP21H05121; JST FOREST Program (JPMJFR200R); Practical Research Project for Allergic Diseases and Immunology (Research on Allergic Diseases and Immunology) from the Japan Agency for Medical Research and Development (AMED) (Nos. JP21ek0410082, JP21ek0410060, and JP19ek0410045); Japan Agency for Medical Research and Development (AMED)-PRIME, AMED (No. JP20gm6110005); Japan Agency for Medical Research and Development (AMED)-CREST, AMED (No. JP20gm1210003); Mochida Memorial Foundation for Medical and Pharmaceutical Research, MSD Life Science Foundation, the Naito Foundation, and the Takeda Science Foundation. P.W.S. was an investigator of the Howard Hughes Medical Institute, which supported this work. We further acknowledge support from the Atkinson Center for a Sustainable Future (to F.C.S. and J.A.A.), the Triad Foundation (to F.C.S.), and NIH CBI training grant T32GM008500 (to J.S.H.). K.S., A.C., and K.H. contributed equally to this work. Author contributions: K.S., A.C., K.H., F.C.S., P.W.S., and T.N. designed research; K.S., A.C., M.K., K.K., T.I., J.S.H., A.S.S., N.B., J.A.A., and R.V.A. performed research; J.S.H., J.A.A., R.V.A., and F.C.S. contributed new reagents/analytic tools; K.S., K.H., M.K., T.I., A.S.S., N.B., F.C.S., and T.N. analyzed data; and K.S., A.C., K.H., F.C.S., and T.N. wrote the paper. Reviewers: R.M., University of Glasgow; and S.Z., Benaroya Research Institute at Virginia Mason. Competing interest statement: The patent rights related to the results reported here have been licensed to Holoclara, Inc., a privately held company that has been pursuing ascr#7-related compounds as potential therapeutics since its founding in 2017. A.C., P.W.S., and F.C.S. are cofounders and stockholders of Holoclara, Inc., and A.C. is the company's chief executive officer. The patent rights have also been licensed to Ascribe Bioscience, Inc., a privately held company where F.C.S. is a cofounder and a stockholder. While most of the studies reported here predate the founding of the company, Holoclara, Inc. funded part of the work. Holoclara, Inc. is not publicly traded and there are no plans for an initial public offering.

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Supplemental Material - 23/2108686119.DCSupplemental/pnas.2108686119.sapp.pdf

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Additional details

Created:
August 22, 2023
Modified:
December 22, 2023