{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:16:05Z","timestamp":1792790165223,"version":"4.5.0"},"reference-count":53,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2024,11,15]],"date-time":"2024-11-15T00:00:00Z","timestamp":1731628800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"CAMS Innovation Fund for Medical Sciences (CIFMS)","award":["2021-1-I2M-035"],"award-info":[{"award-number":["2021-1-I2M-035"]}]},{"name":"CAMS Innovation Fund for Medical Sciences (CIFMS)","award":["2022-I2M-1-011"],"award-info":[{"award-number":["2022-I2M-1-011"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Dengue virus (DENV) infection causes various disease manifestations ranging from an asymptomatic state to severe, life-threatening dengue. Despite intensive research, the molecular mechanisms underlying the abnormal host responses and severe disease symptoms caused by evolved DENV strains is not fully understood. First, the spatial structure of mutant DENV was compared via in silico molecular modeling analysis. Second, employing single-nucleus and spatial RNA sequencing, we analyzed and verified transcriptome samples in uninfected, mild (NGC group), and severe (N10 group) liver tissues from murine models. In this study, we obtained a cumulatively mutated DENV-2 N10 with enhanced capability of replication and pathogenicity post 10 serial passages in Ifnra\u2212\/\u2212 mice. This variant caused severe damage in the liver, as compared with other organs. Furthermore, mutated DENV infection elicited stronger responses in hepatocytes. The critical host factor Nrg4 was identified. It dominated mainly via the activation of the NRG\/ErbB pathway in mice with severe symptoms. We report on evolved N10 viruses with changes observed in different organisms and tissue. This evolutionary variant results in high replicability, severe pathogenicity, and strong responses in murine. Moreover, the host responses may play a role by activating the NRG\/ErbB signaling pathway. Our findings provide a realistic framework for defining disturbed host responses at the animal model level that might be one of the main causes of severe dengue and the potential application value.<\/jats:p>","DOI":"10.3390\/v16111779","type":"journal-article","created":{"date-parts":[[2024,11,15]],"date-time":"2024-11-15T04:47:17Z","timestamp":1731646037000},"page":"1779","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Single-Nucleus and Spatial Transcriptomics Revealing Host Response Differences Triggered by Mutated Virus in Severe Dengue"],"prefix":"10.3390","volume":"16","author":[{"given":"Qian","family":"Chen","sequence":"first","affiliation":[{"name":"Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100021, China"},{"name":"National Center of Technology Innovation for Animal Model, State Key Laboratory of Respiratory Health and Multimorbidity, Key Laboratory of Pathogen Infection Prevention and Control (Peking Union Medical College), Ministry of Education, NHC Key Laboratory of Comparative Medicine, Institute of Laboratory Animal Science, CAMS & PUMC, Beijing 100021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yizhen","family":"Yuan","sequence":"additional","affiliation":[{"name":"Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100021, China"},{"name":"National Center of Technology Innovation for Animal Model, State Key Laboratory of Respiratory Health and Multimorbidity, Key Laboratory of Pathogen Infection Prevention and Control (Peking Union Medical College), Ministry of Education, NHC Key Laboratory of Comparative Medicine, Institute of Laboratory Animal Science, CAMS & PUMC, Beijing 100021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fangzhou","family":"Cai","sequence":"additional","affiliation":[{"name":"Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100021, China"},{"name":"National Center of Technology Innovation for Animal Model, State Key Laboratory of Respiratory Health and Multimorbidity, Key Laboratory of Pathogen Infection Prevention and Control (Peking Union Medical College), Ministry of Education, NHC Key Laboratory of Comparative Medicine, Institute of Laboratory Animal Science, CAMS & PUMC, Beijing 100021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhe","family":"Li","sequence":"additional","affiliation":[{"name":"Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100021, China"},{"name":"National Center of Technology Innovation for Animal Model, State Key Laboratory of Respiratory Health and Multimorbidity, Key Laboratory of Pathogen Infection Prevention and Control (Peking Union Medical College), Ministry of Education, NHC Key Laboratory of Comparative Medicine, Institute of Laboratory Animal Science, CAMS & PUMC, Beijing 100021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Wei","sequence":"additional","affiliation":[{"name":"Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100021, China"},{"name":"National Center of Technology Innovation for Animal Model, State Key Laboratory of Respiratory Health and Multimorbidity, Key Laboratory of Pathogen Infection Prevention and Control (Peking Union Medical College), Ministry of Education, NHC Key Laboratory of Comparative Medicine, Institute of Laboratory Animal Science, CAMS & PUMC, Beijing 100021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100021, China"},{"name":"National Center of Technology Innovation for Animal Model, State Key Laboratory of Respiratory Health and Multimorbidity, Key Laboratory of Pathogen Infection Prevention and Control (Peking Union Medical College), Ministry of Education, NHC Key Laboratory of Comparative Medicine, Institute of Laboratory Animal Science, CAMS & PUMC, Beijing 100021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,11,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1016\/S0140-6736(18)32560-1","article-title":"Dengue","volume":"393","author":"Ooi","year":"2019","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/S1473-3099(22)00798-8","article-title":"Struggling with a new dengue epidemic in Nepal","volume":"23","author":"Pandey","year":"2023","journal-title":"Lancet Infect. 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