TY - JOUR T1 - A helminth chitinase structurally similar to mammalian chitinase displays immunomodulatory properties JF - bioRxiv DO - 10.1101/641837 SP - 641837 AU - Friederike Ebner AU - Katja Balster AU - Katharina Janek AU - Agathe Niewienda AU - Piotr H. Malecki AU - Manfred S. Weiss AU - Tara E. Sutherland AU - Arnd Heuser AU - Anja A. Kühl AU - Jürgen Zentek AU - Andreas Hofmann AU - Susanne Hartmann Y1 - 2019/01/01 UR - http://biorxiv.org/content/early/2019/05/17/641837.abstract N2 - 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.AAMalternatively activated macrophagesAHRairway hyperreactivityAMCaseacidic mammalian chitinaseBALbronchoalveolar lavageChitChitinaseCLPsChitinase-like proteinsESexcretory-secretoryESPexcretory-secretory proteinsGHglycosyl hydrolasesL1fist larval stageLEXSYLeishmania expression systemMSmass spectrometryOVAOvalbuminSPssoluble proteinsTCEPTris(2-carboxyethyl)phosphineT. suisTrichuris suisTs-ChitTrichuris suis chitinaseTs-ESTrichuris suis excretory-secretory proteinsTSOTrichuris suis ovaTTOTrichuris trichiura ovaUCulcerative colitis ER -