Ning Yu, Shigang Chen, Yumeng Liu, Peng Wang, Longlong Wang, Ningning Hu, He Zhang, Xiao Li, Huijun Lu, Ningyi Jin
{"title":"登革病毒血清 1 型感染 AGB6 小鼠模型的致病性和转录组解析。","authors":"Ning Yu, Shigang Chen, Yumeng Liu, Peng Wang, Longlong Wang, Ningning Hu, He Zhang, Xiao Li, Huijun Lu, Ningyi Jin","doi":"10.1002/jmv.29895","DOIUrl":null,"url":null,"abstract":"<p>Dengue viruses are the causative agents of dengue fever, dengue hemorrhagic fever, and dengue shock syndrome, which are mainly transmitted by <i>Aedes aegypti</i> and <i>Aedes albopictus</i> mosquitoes, and cost billions of dollars annually in patient treatment and mosquito control. Progress in understanding DENV pathogenesis and developing effective treatments has been hampered by the lack of a suitable small pathological animal model. Until now, the candidate vaccine, antibody, and drug for DENV have not been effectively evaluated. Here, we analyzed the pathogenicity of DENV-1 in type Ⅰ and type Ⅱ interferon receptor-deficient mice (AGB6) by intraperitoneal inoculation. Infected mice showed such neurological symptoms as opisthotonus, hunching, ataxia, and paralysis of one or both hind limbs. Viremia can be detected 3 days after infection. It was found that 6.98 × 10<sup>3</sup> PFU or higher dose induce 100% mortality. To determine the cause of lethality in mice, heart, liver, spleen, lung, kidney, intestinal, and brain tissues were collected from AGB6 mice (at an attack dose of 6.98 × 10<sup>3</sup> PFU) for RNA quantification, and it was found that the viral load in brain tissues peaked at moribund states (14 dpi) and that the viral loads in the other tissues and organs decreased over time. Significant histopathologic changes were observed in brain tissue (hippocampal region and cerebral cortex). Hematological analysis showed hemorrhage and hemoconcentration in infected mice. DENV-1 can be isolated from the brain tissue of infected mice. Subsequently, brain tissue transcriptome sequencing was performed to assess host response characteristics in infected AGB6 mice. Transcriptional patterns in brain tissue suggest that aberrant expression of pro-inflammatory cytokines induces antiviral responses and tissue damage. Screening of hub genes and their characterization by qPCR and ELISA, it was hypothesized that IL-6 and IFN-γ might be the key factors in dengue virus-induced inflammatory response. Therefore, this study provides an opportunity to decipher certain aspects of dengue pathogenesis further and provides a new platform for drug, antibody, and vaccine testing.</p>","PeriodicalId":16354,"journal":{"name":"Journal of Medical Virology","volume":null,"pages":null},"PeriodicalIF":6.8000,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Pathogenicity and transcriptomic resolution in dengue virus serotype 1 infected AGB6 mouse model\",\"authors\":\"Ning Yu, Shigang Chen, Yumeng Liu, Peng Wang, Longlong Wang, Ningning Hu, He Zhang, Xiao Li, Huijun Lu, Ningyi Jin\",\"doi\":\"10.1002/jmv.29895\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>Dengue viruses are the causative agents of dengue fever, dengue hemorrhagic fever, and dengue shock syndrome, which are mainly transmitted by <i>Aedes aegypti</i> and <i>Aedes albopictus</i> mosquitoes, and cost billions of dollars annually in patient treatment and mosquito control. Progress in understanding DENV pathogenesis and developing effective treatments has been hampered by the lack of a suitable small pathological animal model. Until now, the candidate vaccine, antibody, and drug for DENV have not been effectively evaluated. Here, we analyzed the pathogenicity of DENV-1 in type Ⅰ and type Ⅱ interferon receptor-deficient mice (AGB6) by intraperitoneal inoculation. Infected mice showed such neurological symptoms as opisthotonus, hunching, ataxia, and paralysis of one or both hind limbs. Viremia can be detected 3 days after infection. It was found that 6.98 × 10<sup>3</sup> PFU or higher dose induce 100% mortality. To determine the cause of lethality in mice, heart, liver, spleen, lung, kidney, intestinal, and brain tissues were collected from AGB6 mice (at an attack dose of 6.98 × 10<sup>3</sup> PFU) for RNA quantification, and it was found that the viral load in brain tissues peaked at moribund states (14 dpi) and that the viral loads in the other tissues and organs decreased over time. Significant histopathologic changes were observed in brain tissue (hippocampal region and cerebral cortex). Hematological analysis showed hemorrhage and hemoconcentration in infected mice. DENV-1 can be isolated from the brain tissue of infected mice. Subsequently, brain tissue transcriptome sequencing was performed to assess host response characteristics in infected AGB6 mice. Transcriptional patterns in brain tissue suggest that aberrant expression of pro-inflammatory cytokines induces antiviral responses and tissue damage. Screening of hub genes and their characterization by qPCR and ELISA, it was hypothesized that IL-6 and IFN-γ might be the key factors in dengue virus-induced inflammatory response. Therefore, this study provides an opportunity to decipher certain aspects of dengue pathogenesis further and provides a new platform for drug, antibody, and vaccine testing.</p>\",\"PeriodicalId\":16354,\"journal\":{\"name\":\"Journal of Medical Virology\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":6.8000,\"publicationDate\":\"2024-09-04\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Medical Virology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1002/jmv.29895\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"VIROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Medical Virology","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/jmv.29895","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"VIROLOGY","Score":null,"Total":0}
Pathogenicity and transcriptomic resolution in dengue virus serotype 1 infected AGB6 mouse model
Dengue viruses are the causative agents of dengue fever, dengue hemorrhagic fever, and dengue shock syndrome, which are mainly transmitted by Aedes aegypti and Aedes albopictus mosquitoes, and cost billions of dollars annually in patient treatment and mosquito control. Progress in understanding DENV pathogenesis and developing effective treatments has been hampered by the lack of a suitable small pathological animal model. Until now, the candidate vaccine, antibody, and drug for DENV have not been effectively evaluated. Here, we analyzed the pathogenicity of DENV-1 in type Ⅰ and type Ⅱ interferon receptor-deficient mice (AGB6) by intraperitoneal inoculation. Infected mice showed such neurological symptoms as opisthotonus, hunching, ataxia, and paralysis of one or both hind limbs. Viremia can be detected 3 days after infection. It was found that 6.98 × 103 PFU or higher dose induce 100% mortality. To determine the cause of lethality in mice, heart, liver, spleen, lung, kidney, intestinal, and brain tissues were collected from AGB6 mice (at an attack dose of 6.98 × 103 PFU) for RNA quantification, and it was found that the viral load in brain tissues peaked at moribund states (14 dpi) and that the viral loads in the other tissues and organs decreased over time. Significant histopathologic changes were observed in brain tissue (hippocampal region and cerebral cortex). Hematological analysis showed hemorrhage and hemoconcentration in infected mice. DENV-1 can be isolated from the brain tissue of infected mice. Subsequently, brain tissue transcriptome sequencing was performed to assess host response characteristics in infected AGB6 mice. Transcriptional patterns in brain tissue suggest that aberrant expression of pro-inflammatory cytokines induces antiviral responses and tissue damage. Screening of hub genes and their characterization by qPCR and ELISA, it was hypothesized that IL-6 and IFN-γ might be the key factors in dengue virus-induced inflammatory response. Therefore, this study provides an opportunity to decipher certain aspects of dengue pathogenesis further and provides a new platform for drug, antibody, and vaccine testing.
期刊介绍:
The Journal of Medical Virology focuses on publishing original scientific papers on both basic and applied research related to viruses that affect humans. The journal publishes reports covering a wide range of topics, including the characterization, diagnosis, epidemiology, immunology, and pathogenesis of human virus infections. It also includes studies on virus morphology, genetics, replication, and interactions with host cells.
The intended readership of the journal includes virologists, microbiologists, immunologists, infectious disease specialists, diagnostic laboratory technologists, epidemiologists, hematologists, and cell biologists.
The Journal of Medical Virology is indexed and abstracted in various databases, including Abstracts in Anthropology (Sage), CABI, AgBiotech News & Information, National Agricultural Library, Biological Abstracts, Embase, Global Health, Web of Science, Veterinary Bulletin, and others.