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A helminth chitinase structurally similar to mammalian chitinase displays immunomodulatory properties

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Item Type:Preprint
Title:A helminth chitinase structurally similar to mammalian chitinase displays immunomodulatory properties
Creators Name:Ebner, F. and Balster, K. and Janek, K. and Niewienda, A. and Malecki, P.H. and Weiss, M.S. and Sutherland, T.E. and Heuser, A. and Kühl, A.A. and Zentek, J. and Hofmann, A. and Hartmann, S.
Abstract:Previously, we reported significant immunomodulatory effects of the entire excretory-secretory (ES) proteins of the first larval stage (L1) of the gastrointestinal nematode Trichuris suis in a rodent model of allergic hyperreactivity. In the present study, we aimed to identify the proteins accounting for the modulatory effects of the T. suis L1 ES proteins and thus studied selected components for their immunomodulatory efficacy in an OVA-induced allergic airway disease model. In particular, an enzymatically active T. suis chitinase mediated amelioration of airway hyperreactivity, primarily associated with suppression of eosinophil recruitment into the lung. The three-dimensional structure of the T. suis chitinase as determined by high-resolution X-ray crystallography revealed significant similarities to mouse acidic mammalian chitinase (AMCase). In addition, the unique ability of T. suis chitinase to form dimers, as well as acidic surface patches within the dimerization region may contribute to the formation of cross-reactive antibodies to the mouse homologs. This hypothesis is supported by the observation that T. suis chitinase treatment induced cross-reactive antibodies to mouse AMCase and chitinase-like protein BRP-39 in the AHR model. In conclusion, a biologically active T. suis chitinase exhibits immunomodulatory properties despite its structural similarity to the mammalian counterpart. Author summary: Experimental immunotherapy via reintroduction of intestinal worms to treat and prevent autoimmune, chronic inflammatory or allergic diseases is being discussed but the underlying mechanisms are still not fully understood. Here, we investigated the immunomodulatory potential of specific proteins of the whipworm Trichuris suis that are secreted very early during larval development. Using a murine model of allergic lung disease, we show that in particular one T. suis protein, functionally characterized as an active chitinase, is reducing the lung inflammation. The T. suis chitinases three-dimensional protein structure revealed remarkable similarities to the hosts’ chitinase, an enzyme known to play a pivotal role in lung allergy. We also show that treatment with the helminth chitinase induced cross-reactive antibody responses against murine chitinase and chitinase-like proteins, both being inflammatory marker and regulators of type 2 immunity. Thus, our study provides a novel mechanism of immunomodulation by helminth components and may contribute to a better understanding of clinical responses of patients receiving helminthic therapy.
Keywords:Excretory/Secretory Proteins, Whipworm, Anti Inflammatory Efficacy, Allergic Airway Disease, Protein Dimerization, Parasite-Host Interaction
Publisher:Cold Spring Harbor Laboratory Press
Article Number:641837
Date:17 May 2019
Official Publication:https://doi.org/10.1101/641837

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