Huang Rong Rong, Giafaglione Jenna M, Hashimoto Takao, Zhang Liying, Yu Weibo, Rao Jianyu, Russo Joshua W, Balk Steven P, Nickols Nicholas G, Rettig Mathew B, Goldstein Andrew, Ye Huihui
Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA, USA.
Department of Molecular, Cell & Developmental Biology, University of California, Los Angeles, CA, USA.
J Clin Transl Pathol. 2023;3(2):49-58. doi: 10.14218/jctp.2022.00031. Epub 2023 May 1.
Men have higher morbidity and mortality from COVID-19 than women, possibly due to androgen receptor-regulated viral entry protein expression. This led to a clinical trial of androgen deprivation therapy (ADT), which has not shown a significant benefit in the outcomes among hospitalized male COVID-19 patients. The aim of this study was to explore biological explanations for the failure of ADT to mitigate clinical outcomes in men with severe COVID-19 by assessing the role of androgen in regulating viral entry protein expression in the upper and lower respiratory tract.
Immunohistochemistry was used to assess the expression of transmembrane serine protease 2 (TMPRSS2) and angiotensin-converting enzyme 2 (ACE2) and how it correlated to androgen receptor expression in the sinonasal epithelium, minor salivary glands of the sinus, lacrimal glands, and lungs from mice pretreated with and without castration and ADT as well as the sinonasal epithelium obtained from healthy human donors and hospitalized COVID-19 patients.
In murine models, castration and ADT treatment downregulated the expression of TMPRSS2 and ACE2 in the sinonasal epithelium, minor salivary glands of the sinus, and lacrimal glands, but not in the lungs. Correlative analyses using human tissue also showed a potential role of ADT in men during the early sinonasal phase but not in the later lung phase of SARS-CoV-2 infection.
Our study suggests a potential benefit of ADT in male patients with early COVID-19 when the virus enters the nasopharynx, but not in those with advanced disease. The downregulation of viral entry proteins in the upper respiratory system following androgen blockade may be a key mechanism for this effect.
男性感染新型冠状病毒肺炎（COVID-19）后的发病率和死亡率高于女性，这可能是由于雄激素受体调节病毒进入蛋白的表达所致。这引发了一项雄激素剥夺疗法（ADT）的临床试验，但该试验在住院男性COVID-19患者的治疗结果中并未显示出显著益处。本研究的目的是通过评估雄激素在调节严重COVID-19男性患者上、下呼吸道病毒进入蛋白表达中的作用，探索ADT未能减轻男性严重COVID-19临床结局的生物学原因。
采用免疫组织化学法评估跨膜丝氨酸蛋白酶2（TMPRSS2）和血管紧张素转换酶2（ACE2）的表达，以及其与经去势和ADT预处理及未预处理小鼠的鼻窦上皮、鼻窦小唾液腺、泪腺和肺中雄激素受体表达的相关性，并评估从健康人类供体和住院COVID-19患者获取的鼻窦上皮中的表达情况。
在小鼠模型中，去势和ADT处理下调了鼻窦上皮、鼻窦小唾液腺和泪腺中TMPRSS2和ACE2的表达，但肺中未下调。对人体组织的相关分析也显示，ADT在男性感染严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的鼻窦早期阶段可能发挥作用，但在后期肺部阶段则不然。
我们的研究表明，ADT对病毒进入鼻咽部的早期COVID-19男性患者可能有益，但对病情晚期患者则不然。雄激素阻断后上呼吸道系统中病毒进入蛋白的下调可能是产生这种效果的关键机制。
