Department of Medicine, Washington University School of Medicine , St. Louis, Missouri, USA.
Department of Pathology & Immunology, Washington University School of Medicine , St. Louis, Missouri, USA.
J Virol. 2023 Sep 28;97(9):e0062823. doi: 10.1128/jvi.00628-23. Epub 2023 Sep 7.
The continued evolution and emergence of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants have resulted in challenges to vaccine and antibody efficacy. The emergence of each new variant necessitates the need to re-evaluate and refine animal models used for countermeasure testing. Here, we tested a recently circulating SARS-CoV-2 Omicron lineage variant, BQ.1.1, in multiple rodent models including K18-human ACE2 (hACE2) transgenic, C57BL/6J, and 129S2 mice, and Syrian golden hamsters. In contrast to a previously dominant BA.5.5 Omicron variant, inoculation of K18-hACE2 mice with BQ.1.1 resulted in substantial weight loss, a characteristic seen in pre-Omicron variants. BQ.1.1 also replicated to higher levels in the lungs of K18-hACE2 mice and caused greater lung pathology than the BA.5.5 variant. However, in C57BL/6J mice, 129S2 mice, and Syrian hamsters, BQ.1.1 did not cause increased respiratory tract infection or disease compared to animals administered BA.5.5. Moreover, the rates of direct contact or airborne transmission in hamsters were not significantly different after BQ.1.1 and BA.5.5 infections. Taken together, these data suggest that the BQ.1.1 Omicron variant has increased virulence in rodent species that express hACE2, possibly due to the acquisition of unique spike mutations relative to earlier Omicron variants. IMPORTANCE As severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to evolve, there is a need to rapidly assess the efficacy of vaccines and antiviral therapeutics against newly emergent variants. To do so, the commonly used animal models must also be re-evaluated. Here, we determined the pathogenicity of the BQ.1.1 SARS-CoV-2 variant in multiple SARS-CoV-2 animal models including transgenic mice expressing human ACE2 (hACE2), two strains of conventional laboratory mice, and Syrian hamsters. While BQ.1.1 and BA.5.5 infection resulted in similar levels of viral burden and clinical disease in hamsters and the conventional strains of laboratory mice tested, increases in lung infection were detected in hACE2-expressing transgenic mice, which corresponded with greater levels of pro-inflammatory cytokines and lung pathology. Taken together, our data highlight important differences in two closely related Omicron SARS-CoV-2 variant strains and provide a foundation for evaluating countermeasures.
新型严重急性呼吸系统综合症冠状病毒 2（SARS-CoV-2）变种的持续演变和出现，对疫苗和抗体疗效带来了挑战。每种新变种的出现都需要重新评估和改进用于对策测试的动物模型。在这里，我们在多种啮齿动物模型中测试了最近流行的 SARS-CoV-2 奥密克戎谱系变种 BQ.1.1，包括 K18-人 ACE2（hACE2）转基因、C57BL/6J 和 129S2 小鼠以及叙利亚金黄地鼠。与之前占主导地位的 BA.5.5 奥密克戎变种相比，接种 BQ.1.1 会导致 K18-hACE2 小鼠体重明显减轻，这是在奥密克戎变种之前出现的特征。BQ.1.1 在 K18-hACE2 小鼠肺部的复制水平也更高，并导致比 BA.5.5 变种更大的肺部病理。然而，在 C57BL/6J 小鼠、129S2 小鼠和叙利亚金黄地鼠中，与接种 BA.5.5 的动物相比，BQ.1.1 并未引起呼吸道感染或疾病的增加。此外，在 BQ.1.1 和 BA.5.5 感染后，金黄地鼠之间的直接接触或空气传播率没有显著差异。综上所述，这些数据表明，BQ.1.1 奥密克戎变种在表达 hACE2 的啮齿动物物种中具有更高的毒力，这可能是由于与早期奥密克戎变种相比，其 Spike 突变的独特性。重要性 随着严重急性呼吸系统综合症冠状病毒 2（SARS-CoV-2）的持续演变，需要迅速评估针对新出现变种的疫苗和抗病毒疗法的疗效。为此，还必须重新评估常用的动物模型。在这里，我们在多种 SARS-CoV-2 动物模型中确定了 BQ.1.1 SARS-CoV-2 变种的致病性，包括表达人 ACE2（hACE2）的转基因小鼠、两种常规实验室小鼠株和叙利亚金黄地鼠。虽然 BQ.1.1 和 BA.5.5 感染在金黄地鼠和测试的常规实验室小鼠株中导致相似水平的病毒负担和临床疾病，但在表达 hACE2 的转基因小鼠中检测到肺部感染增加，这与更高水平的促炎细胞因子和肺部病理学相对应。综上所述，我们的数据突出了两种密切相关的奥密克戎 SARS-CoV-2 变种之间的重要差异，并为评估对策提供了基础。
