SARS-CoV-2 Spike Protein Suppresses ACE2 and Type I Interferon Expression in Primary Cells From Macaque Lung Bronchoalveolar Lavage.

Yongjun Sui,Jianping Li,Jay A Berzofsky,David J Venzon

doi:10.3389/fimmu.2021.658428

Abstract

SARS-CoV-2 virus causes upper and lower respiratory diseases including pneumonia, and in some cases, leads to lethal pulmonary failure. Angiotensin converting enzyme-2 (ACE2), the receptor for cellular entry of SARS-CoV-2 virus, has been shown to protect against severe acute lung failure. Here, we provide evidence that SARS-CoV-2 spike protein S1 reduced the mRNA expression of ACE2 and type I interferons in primary cells of lung bronchoalveolar lavage (BAL) from naïve rhesus macaques. The expression levels of ACE2 and type I interferons were also found to be correlated with each other, consistent with the recent finding that ACE2 is an interferon-inducible gene. Furthermore, induction of ACE2 and type I interferons by poly I:C, an interferon inducer, was suppressed by S1 protein in primary cells of BAL. These observations suggest that the downregulation of ACE2 and type I interferons induced by S1 protein may directly contribute to SARS-CoV-2-associated lung diseases.

Highlights

SARS-CoV-2 virus, the causative agent of COVID-19, infects a wide array of cells, including epithelial cells, endothelial cells, and macrophages of multiple organs such as lung, gut, liver and kidneys via angiotensin-converting enzyme 2 (ACE2) as a receptor and transmembrane protease serine 2 (TMPRSS2) as an activating protease [1]
Since the numbers of the primary cells collected from bronchoalveolar lavage (BAL) cells of each animal varied, most of the samples were just enough for control and T1, and only several of them were enough for T2
Because binding of spike protein to the ACE2 receptor on cells can serve to allow viral entry and to trigger an effect on the cells, we asked whether spike-ACE2 signal might affect the innate immune response and trigger either a protective effect or a deleterious response that contributes to immunopathology

Summary

Introduction

SARS-CoV-2 virus, the causative agent of COVID-19, infects a wide array of cells, including epithelial cells, endothelial cells, and macrophages of multiple organs such as lung, gut, liver and kidneys via angiotensin-converting enzyme 2 (ACE2) as a receptor and transmembrane protease serine 2 (TMPRSS2) as an activating protease [1]. In the human respiratory system, ACE2 and TMPRSS2 were primarily expressed in type II pneumocytes and a fraction of secretory cells [1,2,3]. Human virologic and macaque viral challenge studies showed that SARS-CoV-2 virus can productively infect the target cells of upper and lower respiratory airways, which results in a quick peak viral load (2-3 days post viral challenge in macaques) in the lung bronchoalveolar lavage (BAL) fluid [4, 5]. The interplay between the lung immune microenvironment and SARS-CoV-2 virus or its viral components is unclear.

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Conclusion