Single-Nucleus and Spatial Transcriptomics Revealing Host Response Differences Triggered by Mutated Virus in Severe Dengue
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 ful...
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MDPI AG
2024-11-01
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| author | Qian Chen Yizhen Yuan Fangzhou Cai Zhe Li Qiang Wei Wei Wang |
| author_facet | Qian Chen Yizhen Yuan Fangzhou Cai Zhe Li Qiang Wei Wei Wang |
| author_sort | Qian Chen |
| collection | DOAJ |
| description | 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 <i>Ifnra<sup>−/−</sup></i> 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 <i>Nrg4</i> 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. |
| format | Article |
| id | doaj-art-fa55a70b6145493ea8c9ec0abb0ac337 |
| institution | DOAJ |
| issn | 1999-4915 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | MDPI AG |
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| series | Viruses |
| spelling | doaj-art-fa55a70b6145493ea8c9ec0abb0ac3372025-08-20T02:48:10ZengMDPI AGViruses1999-49152024-11-011611177910.3390/v16111779Single-Nucleus and Spatial Transcriptomics Revealing Host Response Differences Triggered by Mutated Virus in Severe DengueQian Chen0Yizhen Yuan1Fangzhou Cai2Zhe Li3Qiang Wei4Wei Wang5Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100021, ChinaInstitute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100021, ChinaInstitute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100021, ChinaInstitute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100021, ChinaInstitute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100021, ChinaInstitute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100021, ChinaDengue 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 <i>Ifnra<sup>−/−</sup></i> 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 <i>Nrg4</i> 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.https://www.mdpi.com/1999-4915/16/11/1779dengue viruscumulative mutationsevere denguesingle-nucleus RNA sequencingspatial transcriptomicsNrg4 |
| spellingShingle | Qian Chen Yizhen Yuan Fangzhou Cai Zhe Li Qiang Wei Wei Wang Single-Nucleus and Spatial Transcriptomics Revealing Host Response Differences Triggered by Mutated Virus in Severe Dengue Viruses dengue virus cumulative mutation severe dengue single-nucleus RNA sequencing spatial transcriptomics Nrg4 |
| title | Single-Nucleus and Spatial Transcriptomics Revealing Host Response Differences Triggered by Mutated Virus in Severe Dengue |
| title_full | Single-Nucleus and Spatial Transcriptomics Revealing Host Response Differences Triggered by Mutated Virus in Severe Dengue |
| title_fullStr | Single-Nucleus and Spatial Transcriptomics Revealing Host Response Differences Triggered by Mutated Virus in Severe Dengue |
| title_full_unstemmed | Single-Nucleus and Spatial Transcriptomics Revealing Host Response Differences Triggered by Mutated Virus in Severe Dengue |
| title_short | Single-Nucleus and Spatial Transcriptomics Revealing Host Response Differences Triggered by Mutated Virus in Severe Dengue |
| title_sort | single nucleus and spatial transcriptomics revealing host response differences triggered by mutated virus in severe dengue |
| topic | dengue virus cumulative mutation severe dengue single-nucleus RNA sequencing spatial transcriptomics Nrg4 |
| url | https://www.mdpi.com/1999-4915/16/11/1779 |
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