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The host mechanism of defense against enteric nematode infection remains to be fully understood, but it involves a polarized type 2 immunity leading to alterations in intestinal function that facilitate worm expulsion. We investigated the role of interleukin-25 (IL-25) in host protection against<jats:named-content content-type=\"genus-species\">Heligmosomoides polygyrus bakeri<\/jats:named-content>infection in mice. Our results showed that<jats:italic>Il25<\/jats:italic>and its receptor subunit,<jats:italic>Il17rb<\/jats:italic>, were upregulated during a primary infection and a secondary challenge infection with<jats:named-content content-type=\"genus-species\">H. polygyrus bakeri<\/jats:named-content>. Genetic deletion of IL-25 (IL-25<jats:sup>\u2212\/\u2212<\/jats:sup>) led to an attenuated type 2 cytokine response and increased worm fecundity in mice with a primary<jats:named-content content-type=\"genus-species\">H. polygyrus bakeri<\/jats:named-content>infection. In addition, the full spectrum of the host memory response against a secondary infection with<jats:named-content content-type=\"genus-species\">H. polygyrus bakeri<\/jats:named-content>was severely impaired in IL-25<jats:sup>\u2212\/\u2212<\/jats:sup>mice, including delayed type 2 cytokine responses, an attenuated functional response of the intestinal smooth muscle and epithelium, diminished intestinal smooth muscle hypertrophy\/hyperplasia, and impaired worm expulsion. Furthermore, exogenous administration of IL-25 restored the host protective memory response against<jats:named-content content-type=\"genus-species\">H. polygyrus bakeri<\/jats:named-content>infection in IL-25<jats:sup>\u2212\/\u2212<\/jats:sup>mice. These data demonstrate that IL-25 is critical for host protective immunity against<jats:named-content content-type=\"genus-species\">H. polygyrus bakeri<\/jats:named-content>infection, highlighting its potential application as a therapeutic agent against parasitic nematode infection worldwide.<\/jats:p>","DOI":"10.1128\/iai.00180-16","type":"journal-article","created":{"date-parts":[[2016,9,13]],"date-time":"2016-09-13T01:59:21Z","timestamp":1473731961000},"page":"3328-3337","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":21,"title":["Critical Role for Interleukin-25 in Host Protective Th2 Memory Response against Heligmosomoides polygyrus bakeri"],"prefix":"10.1128","volume":"84","author":[{"given":"Chenlin","family":"Pei","sequence":"first","affiliation":[{"name":"Department of Radiation Oncology and Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA"},{"name":"Department of 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