• Geraldine Buitrago, Darren Pickering, Roland Ruscher, Cobos CaceresClaudiaCCentre for Molecular Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, Queensland, Australia., Linda Jones, Martha Cooper, Ashley Van Waardenberg, Stephanie Ryan, Kim Miles, Matthew Field, Keith Dredge, Norelle L Daly, Paul R Giacomin, and Alex Loukas.
• Centre for Molecular Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, Queensland, Australia; Centre for Tropical Bioinformatics and Molecular Biology, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, Queensland, Australia.
• Transl Res. 2021 Jun 1; 232: 8810288-102.

AbstractThe symbiotic relationships shared between humans and their gastrointestinal parasites present opportunities to discover novel therapies for inflammatory diseases. A prime example of this phenomenon is the interaction of humans and roundworms such as the hookworm, Necator americanus. Epidemiological observations, animal studies and clinical trials using experimental human hookworm infection show that hookworms can suppress inflammation in a safe and well-tolerated way, and that the key to their immunomodulatory properties lies within their secreted proteome. Herein we describe the identification of 2 netrin domain-containing proteins from the N. americanus secretome, and explore their potential in treating intestinal inflammation in mouse models of ulcerative colitis. One of these proteins, subsequently named Na-AIP-1, was effective at suppressing disease when administered prophylactically in the acute TNBS-induced model of colitis. This protective effect was validated in the more robust CD4 T cell transfer model of chronic colitis, where prophylactic Na-AIP-1 reduced T-cell-dependent type-1 cytokine responses in the intestine and the associated intestinal pathology. Mechanistic studies revealed that depletion of CD11c+ cells abrogated the protective anticolitic effect of Na-AIP-1. Next generation sequencing of colon tissue in the T-cell transfer model of colitis revealed that Na-AIP-1 induced a transcriptomic profile associated with the downregulation of metabolic and signaling pathways involved in type-1 inflammation, notably TNF. Finally, co-culture of Na-AIP-1 with a human monocyte-derived M1 macrophage cell line resulted in significantly reduced secretion of TNF. Na-AIP-1 is now a candidate for clinical development as a novel therapeutic for the treatment of human inflammatory bowel diseases.Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.

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