ACE2吸入作为SARS-CoV-2感染和关注变体中性别偏差差异的治疗靶点。
Inhalation of ACE2 as a therapeutic target on sex-bias differences in SARS-CoV-2 infection and variant of concern.
发表日期：2023 Aug 18
作者：
Yu Onodera, Jady Liang, Yuchong Li, Bryan Griffin, Thenuka Thanabalasingam, Cong Lu, JiaYi Zhu, Mingyao Liu, Theo Moraes, Wenhua Zheng, Jasmin Khateeb, Julie Khang, Yongbo Huang, Mirjana Jerkic, Masaki Nakane, Andrew Baker, Beverley Orser, Ya-Wen Chen, Gerald Wirnsberger, Josef M Penninger, Ori D Rotstein, Arthur S Slutsky, Yimin Li, Samira Mubareka, Haibo Zhang
来源：
Stem Cell Research & Therapy
摘要：
尽管感染率相似，但COVID-19在男性中造成的死亡率高于女性。为了理解这种性别偏倚的疾病严重程度差异背后的潜在机制，我们感染了K18-人类血管紧张素转化酶2（ACE2）雄性和雌性小鼠，感染剂为SARS-CoV-2。我们的研究揭示了雌性小鼠肺部微环境独特的蛋白质表达谱。作为结果，它们对严重感染的易感性较低，具有较高的ACE2表达和较高的雌激素受体α（ERα）/雄激素受体（AR）比例，从而导致抗病毒因子水平增加。在雄性小鼠中，吸入重组ACE2中和病毒，并维持ERα/AR比例，从而保护肺部。我们的发现表明，吸入重组ACE2可以作为SARS-CoV-2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治疗在Delta变异株感染的人类肺器官样板中的潜在有效性。
© 2023 The Authors.
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.© 2023 The Authors.