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Transl. Med."],"published-print":{"date-parts":[[2026,4,8]]},"abstract":"<jats:p>Venezuelan (VEEV), eastern (EEEV), and western (WEEV) equine encephalitis viruses are alphaviruses from different serocomplexes that cause neurological disease in humans. Given their antigenic distance, it has been challenging to isolate cross-reactive antibodies that neutralize infection by multiple medically relevant encephalitic alphaviruses. Recently, distinct entry receptors were identified for these encephalitic alphaviruses: LDLRAD3 for VEEV, VLDLR for EEEV and some strains of WEEV, and PCDH10 for WEEV. Here, using structure-guided mutagenesis, we generated a soluble chimeric protein derived from the LA1 domain of LDLRAD3 and the LA2 domain of VLDLR, termed LDLRAD3-vLA1-VLDLR-LA2, which neutralized infection by VEEV, EEEV, and some WEEV strains in cell culture and protected mice from infection. Structural analysis of this engineered decoy revealed binding to distinct sites on each virus, which corresponded to those engaged by their endogenous entry receptors. We extended the neutralizing and protective capacity to contemporary WEEV strains by adding a single extracellular cadherin domain from sparrow PCDH10 through a stabilized symmetric bispecific decoy scaffold. Our designed receptor decoy serves as a possible countermeasure against multiple encephalitic alphaviruses, and this design platform could be harnessed to develop therapeutic agents against viruses from other families.<\/jats:p>","DOI":"10.1126\/scitranslmed.aec2923","type":"journal-article","created":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T17:59:41Z","timestamp":1775671181000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["Design of a neutralizing and protective pan\u2013encephalitic alphavirus receptor decoy protein"],"prefix":"10.1126","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2222-4553","authenticated-orcid":true,"given":"Sathvik","family":"Palakurty","sequence":"first","affiliation":[{"name":"Department of Pathology &amp; Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA."},{"name":"Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3216-5574","authenticated-orcid":true,"given":"Saravanan","family":"Raju","sequence":"additional","affiliation":[{"name":"Department of Pathology &amp; Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3127-0543","authenticated-orcid":true,"given":"Alan","family":"Sariol","sequence":"additional","affiliation":[{"name":"Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-6070-3261","authenticated-orcid":true,"given":"Ngan","family":"Wagoner","sequence":"additional","affiliation":[{"name":"Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8373-0057","authenticated-orcid":true,"suffix":"Jr.","given":"Theron C.","family":"Gilliland","sequence":"additional","affiliation":[{"name":"Center for Vaccine Research and Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15261, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4506-7842","authenticated-orcid":true,"given":"William B.","family":"Klimstra","sequence":"additional","affiliation":[{"name":"Center for Vaccine Research and Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15261, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8791-3165","authenticated-orcid":true,"given":"Michael S.","family":"Diamond","sequence":"additional","affiliation":[{"name":"Department of Pathology &amp; Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA."},{"name":"Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA."},{"name":"Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO 63110, USA."},{"name":"Center for Vaccines and Immunity to Microbial Pathogens, Washington University School of Medicine, Saint Louis, MO 63110, USA."},{"name":"Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.74.1913.227"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.80.2072.251"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.88.2292.530.a"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.81.15.4702"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20212532"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2915-3"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2024.114809"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-07740-2"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-04326-0"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.09.001"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2204706119"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.3390\/v16111692"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-025-09689-2"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.78.13.6766-6774.2004"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1214441110"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-48989-5"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41422-023-00917-w"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41564-024-01672-3"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2024.151160"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-44872-5"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-025-09500-2"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2525771122"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M000507200"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/41798"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2025.02.036"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2025.115724"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2023.03.032"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-51293-x"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2023.11.031"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03963-9"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03909-1"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-50887-9"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2025.03.029"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41422-024-01031-1"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1093\/protein\/9.7.617"},{"key":"e_1_3_2_37_2","unstructured":"C. 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