A netrin domain-containing protein secreted by the human hookworm Necator americanus protects against CD4 T cell transfer colitis

Buitrago, Geraldine, Pickering, Darren, Ruscher, Roland, Cobos Caceres, Claudia, Jones, Linda, Cooper, Martha, Van Waardenberg, Ashley, Ryan, Stephanie, Miles, Kim, Field, Matthew, Dredge, Keith, Daly, Norelle L., Giacomin, Paul R., and Loukas, Alex (2021) A netrin domain-containing protein secreted by the human hookworm Necator americanus protects against CD4 T cell transfer colitis. Translational Research, 232. pp. 88-102.

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Abstract

The 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.

Item ID: 69080
Item Type: Article (Research - C1)
ISSN: 1878-1810
Copyright Information: © 2021 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)
Funders: National Health and Medical Research Council (NHMRC), Advance Queensland Fellowship (AQF), Paragen Bio (PB), Janssen Research & Development (JR&D), Australian Government (AG), Australian Research Council (ARC)
Projects and Grants: NHMRC program grant (1132975), NHMRC senior principal research fellowship (1117504), PB research contract, JR&D research contract, AG Australian Postgraduate Award, ARC Special Research Initiative award (SRI40200003)
Date Deposited: 23 Aug 2021 00:50
FoR Codes: 32 BIOMEDICAL AND CLINICAL SCIENCES > 3204 Immunology > 320404 Cellular immunology @ 100%
SEO Codes: 28 EXPANDING KNOWLEDGE > 2801 Expanding knowledge > 280102 Expanding knowledge in the biological sciences @ 100%
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