{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T06:29:10Z","timestamp":1791959350875,"version":"4.3.4"},"reference-count":54,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2026,1,4]],"date-time":"2026-01-04T00:00:00Z","timestamp":1767484800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Key Research and Development Program of China","award":["2022YFC2704901"],"award-info":[{"award-number":["2022YFC2704901"]}]},{"name":"Nantong Municipal Key Medical Discipline","award":["L242052"],"award-info":[{"award-number":["L242052"]}]}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["Viruses"],"abstract":"<jats:p>Enterovirus D68 (EV-D68), a neurotropic respiratory pathogen, poses a considerable clinical threat through its link to pediatric acute flaccid myelitis (AFM) and severe respiratory illness. The possibility of recurrent epidemics, evidenced since the 2014 outbreak, remains a major concern. Genomic determinants of virulence are central to this threat. Sequence variations that affect host\u2013receptor interactions, immune evasion, and replication efficiency serve as critical modifiers of pathogenicity. This article systematically reviews the evidence for specific genomic sites that enhance EV-D68 virulence, focusing on three critical regions: the VP1 receptor-binding site, the 2Apro\/TRAF3 cleavage site, and the 3Cpro immunoregulatory region. Mutations in the VP1 receptor-binding site can alter affinity for host receptors such as sialic acid, heparan sulfate, and MFSD6, thereby shaping viral entry and tissue tropism. Alterations in the 2Apro\/TRAF3 cleavage site may impair proteolytic cleavage of host TRAF3, attenuating immune evasion and reducing viral pathogenicity. Variations in the 3Cpro region affect its efficiency in cleaving host proteins involved in translation and autophagy, ultimately modulating viral replication and antiviral responses. Finally, we propose that monitoring for mutations in these key virulence determinants, particularly within the surface-exposed VP1, is essential for effective outbreak preparedness.<\/jats:p>","DOI":"10.3390\/v18010073","type":"journal-article","created":{"date-parts":[[2026,1,5]],"date-time":"2026-01-05T15:28:57Z","timestamp":1767626937000},"page":"73","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Enterovirus D68 Sequence Variations and Pathogenicity: A Review"],"prefix":"10.3390","volume":"18","author":[{"given":"Yi","family":"Zhu","sequence":"first","affiliation":[{"name":"Infectious Disease Department, Children\u2019s Hospital of Fudan University, National Children\u2019s Medical Center, Shanghai 201102, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liting","family":"Wang","sequence":"additional","affiliation":[{"name":"Infectious Disease Department, Children\u2019s Hospital of Fudan University, National Children\u2019s Medical Center, Shanghai 201102, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8759-6921","authenticated-orcid":false,"given":"Jun","family":"Shen","sequence":"additional","affiliation":[{"name":"Infectious Disease Department, Children\u2019s Hospital of Fudan University, National Children\u2019s Medical Center, Shanghai 201102, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e188495","DOI":"10.1172\/JCI188495","article-title":"Immune cells promote paralytic disease in mice infected with enterovirus D68","volume":"135","author":"Lan","year":"2025","journal-title":"J. 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