Onodera Yu, Liang Jady, Li Yuchong, Griffin Bryan, Thanabalasingam Thenuka, Lu Cong, Zhu JiaYi, Liu Mingyao, Moraes Theo, Zheng Wenhua, Khateeb Jasmin, Khang Julie, Huang Yongbo, Jerkic Mirjana, Nakane Masaki, Baker Andrew, Orser Beverley, Chen Ya-Wen, Wirnsberger Gerald, Penninger Josef M, Rotstein Ori D, Slutsky Arthur S, Li Yimin, Mubareka Samira, Zhang Haibo
Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Unity Health Toronto, Toronto, ON, Canada.
Department of Emergency and Critical Care Medicine, Faculty of Medicine, Yamagata University, Yamagata, Japan.
iScience. 2023 Jul 25;26(8):107470. doi: 10.1016/j.isci.2023.107470. eCollection 2023 Aug 18.
Despite similar infection rates, COVID-19 has resulted in more deaths in men than women. To understand the underlying mechanisms behind this sex-biased difference in disease severity, we infected K18-human angiotensin converting enzyme 2 (ACE2) mice of both sexes with SARS-CoV-2. Our study revealed a unique protein expression profile in the lung microenvironment of female mice. As a result, they were less vulnerable to severe infection, with higher ACE2 expression and a higher estrogen receptor α (ERα)/androgen receptor (AR) ratio that led to increased antiviral factor levels. In male mice, inhaling recombinant ACE2 neutralized the virus and maintained the ERα/AR ratio, thereby protecting the lungs. Our findings suggest that inhaling recombinant ACE2 could serve as a decoy receptor against SARS-CoV-2 and protect male mice by offsetting ERα-associated protective mechanisms. Additionally, our study supports the potential effectiveness of recombinant ACE2 therapy in human lung organoids infected with the Delta variant.
尽管感染率相似，但新冠病毒导致的男性死亡人数多于女性。为了解这种疾病严重程度的性别差异背后的潜在机制，我们用新冠病毒感染了雌雄两性的K18-人血管紧张素转换酶2（ACE2）小鼠。我们的研究揭示了雌性小鼠肺微环境中独特的蛋白质表达谱。因此，它们对严重感染的易感性较低，ACE2表达较高，雌激素受体α（ERα）/雄激素受体（AR）比值较高，从而导致抗病毒因子水平升高。在雄性小鼠中，吸入重组ACE2可中和病毒并维持ERα/AR比值，从而保护肺部。我们的研究结果表明，吸入重组ACE2可作为针对新冠病毒的诱饵受体，并通过抵消与ERα相关的保护机制来保护雄性小鼠。此外，我们的研究支持重组ACE2疗法在感染德尔塔变种的人肺类器官中的潜在有效性。
Zotero 插件
