Department of Microbiology, Immunology, and Cell Biology, West Virginia University, Morgantown, WV, United States of America.
Vaccine Development Center at West Virginia University Health Sciences Center, Morgantown, WV, United States of America.
PLoS One. 2022 Aug 29;17(8):e0273430. doi: 10.1371/journal.pone.0273430. eCollection 2022.
The COVID-19 pandemic has been fueled by SARS-CoV-2 novel variants of concern (VOC) that have increased transmissibility, receptor binding affinity, and other properties that enhance disease. The goal of this study is to characterize unique pathogenesis of the Delta VOC strain in the K18-hACE2-mouse challenge model. Challenge studies suggested that the lethal dose of Delta was higher than Alpha or Beta strains. To characterize the differences in the Delta strain's pathogenesis, a time-course experiment was performed to evaluate the overall host response to Alpha or Delta variant challenge. qRT-PCR analysis of Alpha- or Delta-challenged mice revealed no significant difference between viral RNA burden in the lung, nasal wash or brain. However, histopathological analysis revealed high lung tissue inflammation and cell infiltration following Delta- but not Alpha-challenge at day 6. Additionally, pro-inflammatory cytokines were highest at day 6 in Delta-challenged mice suggesting enhanced pneumonia. Total RNA-sequencing analysis of lungs comparing challenged to no challenge mice revealed that Alpha-challenged mice have more total genes differentially activated. Conversely, Delta-challenged mice have a higher magnitude of differential gene expression. Delta-challenged mice have increased interferon-dependent gene expression and IFN-γ production compared to Alpha. Analysis of TCR clonotypes suggested that Delta challenged mice have increased T-cell infiltration compared to Alpha challenged. Our data suggest that Delta has evolved to engage interferon responses in a manner that may enhance pathogenesis. The in vivo and in silico observations of this study underscore the need to conduct experiments with VOC strains to best model COVID-19 when evaluating therapeutics and vaccines.
COVID-19 大流行是由 SARS-CoV-2 新型关注变种（VOC）推动的，这些变种增加了传染性、受体结合亲和力和其他增强疾病的特性。本研究的目的是在 K18-hACE2-小鼠挑战模型中表征 Delta VOC 株的独特发病机制。挑战研究表明，Delta 的致死剂量高于 Alpha 或 Beta 株。为了表征 Delta 株发病机制的差异，进行了时间过程实验，以评估宿主对 Alpha 或 Delta 变异体挑战的总体反应。qRT-PCR 分析表明，在感染 Alpha 或 Delta 的小鼠的肺部、鼻腔冲洗液或大脑中，病毒 RNA 负担没有显著差异。然而，组织病理学分析显示，Delta 感染后第 6 天肺部组织炎症和细胞浸润明显高于 Alpha 感染。此外，Delta 感染小鼠在第 6 天的促炎细胞因子最高，表明肺炎加重。对感染和未感染小鼠的肺部进行总 RNA 测序分析表明，与 Alpha 感染相比，Alpha 感染的小鼠有更多的总基因差异激活。相反，Delta 感染的小鼠具有更高幅度的差异基因表达。与 Alpha 相比，Delta 感染的小鼠干扰素依赖性基因表达和 IFN-γ 产生增加。TCR 克隆型分析表明，与 Alpha 感染相比，Delta 感染的小鼠 T 细胞浸润增加。我们的数据表明，Delta 已经进化为以增强发病机制的方式参与干扰素反应。本研究的体内和计算机模拟观察强调了在评估治疗方法和疫苗时，需要用 VOC 株进行实验，以最好地模拟 COVID-19。
