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We identified a short sequence, termed truncated Bm5339, that has structural similarities to the human IL-10 functional dimer. Sequence comparisons revealed that other filarial parasites possess Bm5539 orthologues. Using recombinant Bm5539 in a modified Luciferase Immunoprecipitation System assay, we confirmed that both the truncated and full-length forms of the protein can bind to human IL-10R1. Truncated Bm5539 could inhibit human IL-10-driven phosphorylation of STAT3, thereby demonstrating that Bm5539 acts as an IL-10 antagonist, most likely through competitive binding to the receptor. We provide a structural basis for these observations using computational modeling and simulations. This parasite-encoded cytokine receptor antagonist provides an additional lens through which parasite-induced modulation of the host immune response can be examined.<\/jats:p>","DOI":"10.1093\/pnasnexus\/pgac184","type":"journal-article","created":{"date-parts":[[2022,9,7]],"date-time":"2022-09-07T15:03:06Z","timestamp":1662562986000},"source":"Crossref","is-referenced-by-count":2,"title":["A filarial parasite-encoded human IL-10 receptor antagonist reveals a novel strategy to modulate host responses"],"prefix":"10.1093","volume":"1","author":[{"given":"Alessandra","family":"Ricciardi","sequence":"first","affiliation":[{"name":"Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases , Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3319-078X","authenticated-orcid":false,"given":"Sergio A","family":"Hassan","sequence":"additional","affiliation":[{"name":"Bioinformatics and Computational Biosciences Branch, National Institute of Allergy and Infectious Diseases , Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Olena","family":"Kamenyeva","sequence":"additional","affiliation":[{"name":"Research Technology Branch, National Institute of Allergy and Infectious Diseases , Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sasisekhar","family":"Bennuru","sequence":"additional","affiliation":[{"name":"Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases , Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John","family":"Andersen","sequence":"additional","affiliation":[{"name":"Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases , 12735 Twinbrook Parkway, Rockville, MD 20852, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6887-4941","authenticated-orcid":false,"given":"Thomas B","family":"Nutman","sequence":"additional","affiliation":[{"name":"Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases , Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2022,9,7]]},"reference":[{"key":"2023012714325404300_bib1","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1086\/524301","article-title":"CD4(+) (and not CD25+) T cells are the predominant interleukin-10-producing cells in the circulation of filaria-infected patients","volume":"197","author":"Mitre","year":"2008","journal-title":"J Infect Dis"},{"key":"2023012714325404300_bib2","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1016\/j.imbio.2007.03.009","article-title":"Chronic helminth infections induce immunomodulation: consequences and mechanisms","volume":"212","author":"van\u00a0Riet","year":"2007","journal-title":"Immunobiology"},{"key":"2023012714325404300_bib3","doi-asserted-by":"crossref","first-page":"1516","DOI":"10.1172\/JCI112982","article-title":"Parasite-specific anergy in human filariasis. 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