British Columbia Centre for Disease Control, Vancouver, BC V5Z 4R4, Canada; School of Population and Public Health, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
British Columbia Centre for Disease Control, Vancouver, BC V5Z 4R4, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
EBioMedicine. 2021 Apr;66:103316. doi: 10.1016/j.ebiom.2021.103316. Epub 2021 Apr 2.
Angiotensin converting enzyme 2 (ACE2) protein serves as the host receptor for SARS-CoV-2, with a critical role in viral infection. We aim to understand population level variation of nasopharyngeal ACE2 transcription in people tested for COVID-19 and the relationship between ACE2 transcription and SARS-CoV-2 viral load, while adjusting for expression of: (i) the complementary protease, Transmembrane serine protease 2 (TMPRSS2), (ii) soluble ACE2, (iii) age, and (iv) biological sex. The ACE2 gene was targeted to measure expression of transmembrane and soluble transcripts.
A cross-sectional study of n = 424 "participants" aged 1-104 years referred for COVID-19 testing was performed in British Columbia, Canada. Patients who tested positive for COVID-19 were matched by age and biological sex to patients who tested negative. Viral load and host gene expression were assessed by quantitative reverse-transcriptase polymerase chain reaction. Bivariate analysis and multiple linear regression were performed to understand the role of nasopharyngeal ACE2 expression in SARS-CoV-2 infection.
Analysis showed no association between age and nasopharyngeal ACE2 transcription in those who tested negative for COVID-19 (P = 0•092). Mean relative transcription of transmembrane (P = 0•00012) and soluble (P<0•0001) ACE2 isoforms, as well as TMPRSS2 (P<0•0001) was higher in COVID-19-negative participants than COVID--19 positive ones, yielding a negative correlation between targeted host gene expression and positive COVID-19 diagnosis. In bivariate analysis of COVID-19-positive participants, transcription of transmembrane ACE2 positively correlated with SARS-CoV-2 viral RNA load (B = 0•49, R=0•14, P<0•0001), transcription of soluble ACE2 negatively correlated (B= -0•85, R= 0•26, P<0•0001), and no correlation was found with TMPRSS2 transcription (B= -0•042, R=<0•10, P = 0•69). Multivariable analysis showed that the greatest viral RNA loads were observed in participants with high transmembrane ACE2 transcription (Β= 0•89, 95%CI: [0•59 to 1•18]), while transcription of the soluble isoform appears to protect against high viral RNA load in the upper respiratory tract (Β= -0•099, 95%CI: [-0•18 to -0•022]).
Nasopharyngeal ACE2 transcription plays a dual, contrasting role in SARS-CoV-2 infection of the upper respiratory tract. Transcription of the transmembrane ACE2 isoform positively correlates, while transcription of the soluble isoform negatively correlates with viral RNA load after adjusting for age, biological sex, and transcription of TMPRSS2.
This project (COV-55) was funded by Genome British Columbia as part of their COVID-19 rapid response initiative.
血管紧张素转换酶 2（ACE2）蛋白是 SARS-CoV-2 的宿主受体，在病毒感染中起关键作用。我们旨在了解在检测 COVID-19 的人群中，鼻咽 ACE2 转录的人群水平变化，以及 ACE2 转录与 SARS-CoV-2 病毒载量之间的关系，同时调整以下因素的表达：（i）互补蛋白酶，跨膜丝氨酸蛋白酶 2（TMPRSS2），（ii）可溶性 ACE2，（iii）年龄和（iv）生物学性别。ACE2 基因被靶向以测量跨膜和可溶性转录物的表达。
在加拿大不列颠哥伦比亚省进行了一项针对 424 名年龄在 1-104 岁的“参与者”的横断面研究，这些人因 COVID-19 检测而被转诊。将 COVID-19 检测呈阳性的患者与年龄和生物学性别相匹配的 COVID-19 检测呈阴性的患者相匹配。通过定量逆转录聚合酶链反应评估病毒载量和宿主基因表达。进行了双变量分析和多元线性回归，以了解鼻咽 ACE2 表达在 SARS-CoV-2 感染中的作用。
分析显示，在 COVID-19 检测呈阴性的人群中，年龄与鼻咽 ACE2 转录之间无关联（P=0.092）。跨膜（P=0.00012）和可溶性（P<0.0001）ACE2 同工型以及 TMPRSS2（P<0.0001）的相对转录均值在 COVID-19 阴性参与者中更高，导致靶向宿主基因表达与 COVID-19 阳性诊断呈负相关。在 COVID-19 阳性参与者的双变量分析中，跨膜 ACE2 转录与 SARS-CoV-2 病毒 RNA 载量呈正相关（B=0.49，R=0.14，P<0.0001），可溶性 ACE2 转录呈负相关（B=-0.85，R=0.26，P<0.0001），而与 TMPRSS2 转录无相关性（B=-0.042，R=<0.10，P=0.69）。多变量分析显示，高跨膜 ACE2 转录的参与者中观察到最大的病毒 RNA 载量（Β=0.89，95%CI：[0.59 至 1.18]），而可溶性同工型的转录似乎可防止上呼吸道的高病毒 RNA 载量（Β=-0.099，95%CI：[-0.18 至 -0.022]）。
鼻咽 ACE2 转录在 SARS-CoV-2 对上呼吸道的感染中起双重、相反的作用。在调整年龄、生物学性别和 TMPRSS2 转录后，跨膜 ACE2 同工型的转录呈正相关，而可溶性同工型的转录与病毒 RNA 载量呈负相关。
该项目（COV-55）由英属哥伦比亚基因组组织资助，作为其 COVID-19 快速反应倡议的一部分。
