Novel antiinflammatory biologics shaped by parasite–host coevolution

Ryan, S. M. et al. (2022) Novel antiinflammatory biologics shaped by parasite–host coevolution. Proceedings of the National Academy of Sciences of the United States of America, 119(36), e220279511. (doi: 10.1073/pnas.2202795119) (PMID:36037362)

Abstract

Parasitic helminth infections, while a major cause of neglected tropical disease burden, negatively correlate with the incidence of immune-mediated inflammatory diseases such as inflammatory bowel diseases (IBD). To evade expulsion, helminths have developed sophisticated mechanisms to regulate their host’s immune responses. Controlled experimental human helminth infections have been assessed clinically for treating inflammatory conditions; however, such a radical therapeutic modality has challenges. An alternative approach is to harness the immunomodulatory properties within the worm’s excretory–secretory (ES) complement, its secretome. Here, we report a biologics discovery and validation pipeline to generate and screen in vivo a recombinant cell-free secretome library of helminth-derived immunomodulatory proteins. We successfully expressed 78 recombinant ES proteins from gastrointestinal hookworms and screened the crude in vitro translation reactions for anti-IBD properties in a mouse model of acute colitis. After statistical filtering and ranking, 20 proteins conferred significant protection against various parameters of colitis. Lead candidates from distinct protein families, including annexins, transthyretins, nematode-specific retinol-binding proteins, and SCP/TAPS were identified. Representative proteins were produced in mammalian cells and further validated, including ex vivo suppression of inflammatory cytokine secretion by T cells from IBD patient colon biopsies. Proteins identified herein offer promise as novel, safe, and mechanistically differentiated biologics for treating the globally increasing burden of inflammatory diseases.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Kennedy, Professor Malcolm and Smith, Dr Brian
• Authors: Ryan, S. M., Ruscher, R., Johnston, W. A., Pickering, D. A., Kennedy, M. W., Smith, B. O., Jones, L., Buitrago, G., Field, M. A., Esterman, A. J., McHugh, C. P., Browne, D. J., Cooper, M. M., Ryan, R. Y. M., Doolan, D. L., Engwerda, C. R., Miles, K., Mitreva, M., Croese, J., Rahman, T., Alexandrov, K., Giacomin, P. R., and Loukas, A.
• College/School: College of Medical Veterinary and Life Sciences > School of Biodiversity, One Health & Veterinary Medicine; College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
• Journal Name: Proceedings of the National Academy of Sciences of the United States of America
• Publisher: National Academy of Sciences
• ISSN: 0027-8424
• ISSN (Online): 1091-6490
• Published Online: 29 August 2022
• Copyright Holders: Copyright © 2022 The Author(s)
• First Published: First published in Proceedings of the National Academy of Sciences of the United States of America 119(36): e220279511
• Publisher Policy: Reproduced under a Creative Commons license