{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T19:01:13Z","timestamp":1790103673664,"version":"4.0.1"},"reference-count":39,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T00:00:00Z","timestamp":1789776000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006245","name":"National Science and Technology Major Project for the Prevention and Control of Emerging and Major Infectious Diseases","doi-asserted-by":"publisher","award":["2026ZD01908801"],"award-info":[{"award-number":["2026ZD01908801"]}],"id":[{"id":"10.13039\/501100006245","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"publisher","award":["2024M754296"],"award-info":[{"award-number":["2024M754296"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]},{"award":["2024M754296"],"award-info":[{"award-number":["2024M754296"]}],"id":[{"id":"https:\/\/ror.org\/0426zh255","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82341116"],"award-info":[{"award-number":["82341116"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["82341116"],"award-info":[{"award-number":["82341116"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pathogens"],"abstract":"<jats:p>The E2 glycoprotein of chikungunya virus (CHIKV) binds negatively charged cell-surface heparan sulfate (HS) to facilitate viral attachment and modulate pathogenicity, yet the E2 determinants governing HS-dependent attachment and the effects of altered HS utilization on subsequent infection remain incompletely defined. From a low-passage clinical isolate obtained during the 2010 Guangdong outbreak, we identified a previously unreported E2 substitution, N218K, which introduces a basic residue. In vitro, this mutation enhanced early infection and attachment to mammalian cells and reduced the RNA\/PFU ratio; in A129 mice, however, it reduced early serum viral RNA levels, was associated with lower tissue viral RNA burdens at 5 dpi, and delayed mortality, consistent with partial attenuation. Soluble HS competition assays showed that N218K increased HS dependence during viral attachment, whereas DEAE-dextran assays supported a role for charge-dependent interactions in restricting local viral spread. N218K also enhanced viral internalization after normalization of initial attachment, identifying an additional post-attachment phenotype associated with this substitution. Our findings identify N218K as a determinant of HS-dependent attachment and partial attenuation in A129 mice, reveal a \u201chigh attachment\u2013low dissemination\u201d phenotype, and further show that this charge-altering E2 substitution enhances post-attachment internalization.<\/jats:p>","DOI":"10.3390\/pathogens15090993","type":"journal-article","created":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T17:56:41Z","timestamp":1790099801000},"page":"993","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Chikungunya Virus E2 N218K Enhances Heparan Sulfate-Dependent Attachment and Viral Internalization While Conferring Partial Attenuation in A129 Mice"],"prefix":"10.3390","volume":"15","author":[{"given":"Teng","family":"Chen","sequence":"first","affiliation":[{"name":"State Key Laboratory of Pathogen and Biosecurity, Academy of Military Medical Sciences, Beijing 100071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Pathogen and Biosecurity, Academy of Military Medical Sciences, Beijing 100071, China"},{"name":"Kunming Angel Women and Children\u2019s Hospital, Kunming 650032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zherui","family":"Zhang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Virology and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430062, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenglin","family":"Deng","sequence":"additional","affiliation":[{"name":"Key Laboratory of Virology and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430062, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Virology and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430062, China"},{"name":"University of Chinese Academy of Sciences, Beijing 100049, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin-Can","family":"Peng","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Pathogen and Biosecurity, Academy of Military Medical Sciences, Beijing 100071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Xin","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Pathogen and Biosecurity, Academy of Military Medical Sciences, Beijing 100071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nan","family":"Chen","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Pathogen and Biosecurity, Academy of Military Medical Sciences, Beijing 100071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3917-8100","authenticated-orcid":false,"given":"Xing-Yao","family":"Huang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Pathogen and Biosecurity, Academy of Military Medical Sciences, Beijing 100071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2500344","DOI":"10.2807\/1560-7917.ES.2025.30.22.2500344","article-title":"Genomic insights into the re-emergence of chikungunya virus on R\u00e9union Island, France, 2024 to 2025","volume":"30","author":"Frumence","year":"2025","journal-title":"Euro Surveill."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"taaf055","DOI":"10.1093\/jtm\/taaf055","article-title":"Resurgence of chikungunya in the Indian Ocean region in 2024\u20132025","volume":"32","author":"Huits","year":"2025","journal-title":"J. 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