Department of Pharmacology, New York Medical College, Valhalla, New York, USA.
Department of Pathology, Microbiology and Immunology, New York Medical College, Valhalla, New York, USA.
Br J Pharmacol. 2023 Oct;180(20):2677-2693. doi: 10.1111/bph.16155. Epub 2023 Jul 5.
COVID-19 infections caused by SARS-CoV-2 disseminated through human-to-human transmission can evoke severe inflammation. Treatments to reduce the SARS-CoV-2-associated inflammation are needed and are the focus of much research. In this study, we investigated the effect of N-ethyl-N'-[(3β,5α)-17-oxoandrostan-3-yl] urea (NEOU), a novel 17α-ketosteroid derivative, on the severity of COVID-19 infections.
Studies were conducted in SARS-CoV-2-infected K18-hACE2 mice.
SARS-CoV-2-infected K18-hACE2 mice developed severe inflammatory crises and immune responses along with up-regulation of genes in associated signalling pathways in male more than female mice. Notably, SARS-CoV-2 infection down-regulated genes encoding drug metabolizing cytochrome P450 enzymes in male but not female mice. Treatment with NEOU (1 mg·kg ·day ) 24 or 72 h post-viral infection alleviated lung injury by decreasing expression of genes encoding inflammatory cytokines and chemokines while increasing expression of genes encoding immunoglobins. In situ hybridization using RNA scope™ probes and immunohistochemical assays revealed that NEOU increased resident CD169 immunoregulatory macrophages and IBA-1 immunoreactive macrophage-dendritic cells within alveolar spaces in the lungs of infected mice. Consequentially, NEOU reduced morbidity more prominently in male than female mice. However, NEOU increased median survival time and accelerated recovery from infection by 6 days in both males and females.
These findings demonstrate that SARS-CoV-2 exhibits gender bias by differentially regulating genes encoding inflammatory cytokines, immunogenic factors and drug-metabolizing enzymes, in male versus female mice. Most importantly, we identified a novel 17α-ketosteroid that reduces the severity of COVID-19 infection and could be beneficial for reducing impact of COVID-19.
由 SARS-CoV-2 引起的 COVID-19 感染通过人际传播扩散，可引发严重炎症。需要寻找减轻 SARS-CoV-2 相关炎症的治疗方法，这也是目前研究的重点。在本研究中，我们研究了新型 17α-酮甾体衍生物 N-乙基-N'-[(3β,5α)-17-氧代雄甾烷-3-基]脲（NEOU）对 COVID-19 感染严重程度的影响。
本研究在感染 SARS-CoV-2 的 K18-hACE2 小鼠中进行。
感染 SARS-CoV-2 的 K18-hACE2 雄性小鼠比雌性小鼠更易出现严重的炎症危机和免疫反应，相关信号通路中的基因表达上调。值得注意的是，SARS-CoV-2 感染下调了雄性而非雌性小鼠编码药物代谢细胞色素 P450 酶的基因。病毒感染后 24 或 72 小时给予 NEOU（1mg·kg-1·day-1）治疗可通过降低炎症细胞因子和趋化因子的基因表达，增加免疫球蛋白的基因表达，减轻肺部损伤。使用 RNA scope™探针原位杂交和免疫组化分析显示，NEOU 增加了感染小鼠肺泡内固有 CD169 免疫调节巨噬细胞和 IBA-1 免疫反应性巨噬细胞-树突状细胞的数量。因此，NEOU 更显著地降低了雄性小鼠的发病率，而对雌性小鼠的影响较小。然而，NEOU 使雄性和雌性小鼠的中位生存时间分别增加了 6 天，且加速了感染恢复。
这些发现表明，SARS-CoV-2 通过在雄性和雌性小鼠中差异调节编码炎症细胞因子、免疫原性因子和药物代谢酶的基因，表现出性别偏向。最重要的是，我们鉴定了一种新型 17α-酮甾体，可减轻 COVID-19 感染的严重程度，有助于降低 COVID-19 的影响。
