College of Veterinary Medicine, Jilin University, Changchun, China.
Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, China.
J Med Virol. 2024 Sep;96(9):e29895. doi: 10.1002/jmv.29895.
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 × 10 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 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.
登革热病毒是登革热、登革出血热和登革休克综合征的病原体，主要通过埃及伊蚊和白纹伊蚊传播，每年在患者治疗和蚊虫控制方面花费数十亿美元。对 DENV 发病机制的理解和有效治疗方法的进展受到缺乏合适的小病理动物模型的阻碍。到目前为止，候选疫苗、抗体和药物对 DENV 的疗效尚未得到有效评估。在这里，我们通过腹腔接种分析了 I 型和 II 型干扰素受体缺陷型小鼠（AGB6）中 DENV-1 的致病性。感染的小鼠表现出角弓反张、蜷缩、共济失调和一条或两条后肢瘫痪等神经症状。感染后 3 天可检测到病毒血症。结果发现，感染剂量为 6.98×10PFU 或更高时可导致 100%的死亡率。为了确定导致小鼠死亡的原因，从 AGB6 小鼠（攻击剂量为 6.98×10PFU）的心、肝、脾、肺、肾、肠和脑组织中收集 RNA 进行定量，并发现脑组织中的病毒载量在濒死状态（14dpi）时达到峰值，而其他组织和器官中的病毒载量随时间减少。在脑组织（海马区和大脑皮层）中观察到明显的组织病理学变化。血液学分析显示感染小鼠有出血和血液浓缩。可以从感染小鼠的脑组织中分离出 DENV-1。随后，对感染的 AGB6 小鼠的脑组织进行了转录组测序，以评估宿主的反应特征。脑组织的转录模式表明，促炎细胞因子的异常表达诱导抗病毒反应和组织损伤。通过 qPCR 和 ELISA 对关键基因进行筛选和表征，假设 IL-6 和 IFN-γ 可能是登革病毒诱导的炎症反应的关键因素。因此，本研究为进一步阐明登革热发病机制提供了机会，并为药物、抗体和疫苗的检测提供了新的平台。
