The Contrasting Role of Nasopharyngeal Angiotensin Converting Enzyme 2 (ACE2) Expression in SARS-CoV-2 Infection: A Cross-Sectional Study of People Tested for COVID-19 in British Columbia

Abstract

SummaryBackgroundAngiotensin converting enzyme 2 (ACE2) 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 expression in people tested for COVID-19 and the relationship between ACE2 expression and SARS-CoV-2 viral RNA load, while adjusting for expression of the complementary protease, Transmembrane serine protease 2 (TMPRSS2), soluble ACE2, age, and biological sex.MethodsA cross-sectional study of n=424 participants aged 1-104 years referred for COVID-19 testing was performed in British Columbia, Canada. Participants who tested negative or positive for COVID-19 were matched by age and biological sex. Viral and host gene expression was measured 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. The ACE2 gene was targeted to measure expression of transmembrane and soluble transcripts.FindingsAnalysis shows no association between age and nasopharyngeal ACE2 expression in those who tested negative for COVID-19 (P=0·092). Mean expression of transmembrane (P=1·2e-4), soluble ACE2 (P<0·0001) and TMPRSS2 (P<0·0001) differed between COVID-19-negative and -positive groups. In bivariate analysis of COVID-19-positive participants, expression of transmembrane ACE2 positively correlated with SARS-CoV-2 RNA viral load (P<0·0001), expression of soluble ACE2 negatively correlated (P<0·0001), and no correlation was found with TMPRSS2 (P=0·694). Multivariable analysis showed that the greatest viral RNA loads were observed in participants with high transmembrane ACE2 expression (B=0·886, 95%CI:[0·596 to 1·18]), while expression of soluble ACE2 may protect against high viral RNA load in the upper respiratory tract (B= −0·0990, 95%CI:[−0·176 to −0·0224]).InterpretationNasopharyngeal ACE2 expression plays a dual, contrasting role in SARS-CoV-2 infection of the upper respiratory tract. Transmembrane ACE2 positively correlates, while soluble ACE2 negatively correlates with viral RNA load after adjusting for age, biological sex and expression of TMPRSS2.FundingThis project (COV-55) was funded by Genome British Columbia as part of their COVID-19 rapid response initiative.