Replication-dependent downregulation of cellular angiotensin-converting enzyme 2 protein expression by human coronavirus NL63

Dijkman, Ronald; Jebbink, Maarten F.; Deijs, Martin; Milewska, Aleksandra; Pyrć, Krzysztof; Buelow, Elena; Bijl, Anna van der; Hoek, Lia van der

doi:10.1099/vir.0.043919-0

Cited by 134 publications

(125 citation statements)

References 39 publications

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“…Furthermore, in contrast to HCoV-NL63 infection, SARS-CoV infection results in a marked downregulation of ACE2 expression on the cell surface, thereby disrupting RAS homeostasis; this in itself may cause severe lung injury (20). Dijkman et al showed that ACE2 expression was downregulated upon HCoV-NL63 infection although the result was heavily dependent upon the infection efficiency (52). Based on these reports, one wonders whether ACE2 is actually the cellular receptor for HCoV-NL63.…”

Section: Discussionmentioning

confidence: 99%

Human Coronavirus NL63 Utilizes Heparan Sulfate Proteoglycans for Attachment to Target Cells

Milewska

Zarębski

Nowak

et al. 2014

J Virol

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287

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Human coronavirus NL63 (HCoV-NL63) is an alphacoronavirus that was first identified in 2004 in the nasopharyngeal aspirate from a 7-month-old patient with a respiratory tract infection. Previous studies showed that HCoV-NL63 and the genetically distant severe acute respiratory syndrome (SARS)-CoV employ the same receptor for host cell entry, angiotensin-converting enzyme 2 (ACE2), but it is largely unclear whether ACE2 interactions are sufficient to allow HCoV-NL63 binding to cells. The present study showed that directed expression of angiotensin-converting enzyme 2 (ACE2) on cells previously resistant to HCoV-NL63 renders them susceptible, showing that ACE2 protein acts as a functional receptor and that its expression is required for infection. However, comparative analysis showed that directed expression or selective scission of the ACE2 protein had no measurable effect on virus adhesion. In contrast, binding of HCoV-NL63 to heparan sulfates was required for viral attachment and infection of target cells, showing that these molecules serve as attachment receptors for HCoV-NL63. IMPORTANCE ACE2 protein was proposed as a receptor for HCoV-NL63 already in 2005, but an in-depth analysis of early events during virus infection had not been performed thus far.Here, we show that the ACE2 protein is required for viral entry but that it is not the primary binding site on the cell surface. Conducted research showed that heparan sulfate proteoglycans function as adhesion molecules, increasing the virus density on cell surface and possibly facilitating the interaction between HCoV-NL63 and its receptor. Obtained results show that the initial events during HCoV-NL63 infection are more complex than anticipated and that a newly described interaction may be essential for understanding the infection process and, possibly, also assist in drug design.

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Section: Discussionmentioning

confidence: 99%

Human Coronavirus NL63 Utilizes Heparan Sulfate Proteoglycans for Attachment to Target Cells

Milewska

Zarębski

Nowak

et al. 2014

J Virol

Self Cite

287

335

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“…45 Continued viral infection and replication contribute to reduced membrane ACE2 expression, at least in vitro in cultured cells. 46 Down-regulation of ACE2 activity in the lungs facilitates the initial neutrophil infiltration in response to bacterial endotoxin 47 and may result in unopposed angiotensin II accumulation and local RAAS activation. Indeed, in experimental mouse models, exposure to SARS-CoV-1 spike protein induced acute lung injury, which is limited by RAAS blockade.…”

Section: P Otential For Benefit R Ather Than Harm Of R a A S Blockersmentioning

confidence: 99%

Renin–Angiotensin–Aldosterone System Inhibitors in Patients with Covid-19

et al. 2020

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“…SARS-CoV2, SARS-CoV, and HCoV-NL63, a virus that causes a mild respiratory infection, are all known to employ ACE2 as a receptor (3,4,16,17). Given the functions of ACE2 in the cardiovascular system, the importance of angiotensin-directed pharmacology in cardiovascular disease and the apparent propensity for severe illness among patients with COVID-19 with cardiovascular comorbidity, the ACE2 molecule has been the subject of much attention (18).…”

Section: Pathogenesis: Angiotensin-converting Enzymementioning

confidence: 99%

COVID-19 for the Cardiologist

Atri

Siddiqi

Lang

et al. 2020

JACC: Basic to Translational Science

268

137

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Highlights-Severe acute respiratory virus-2 (SARS-CoV2), the infection responsible for coronavirus disease-2019 (COVID-19), has spread globally leading to a devastating loss of life. In a few short months, the clinical and scientific communities have rallied to rapidly evolve our understanding of the mechanism(s) of disease and potential therapeutics. -This review discusses the current understanding of the basis virology of SARS-CoV2 and the epidemiology, clinical manifestations, including cardiovascular, and mortality of COVID-19. A detailed review of the viral life cycle and putative mechanism(s) of injury frames the discussion of possible preventative and therapeutic strategies. -The ongoing, unprecedented collective effort will, without a doubt, advance our ability to prevent the spread and optimally care for patients suffering from COVID-19. SummaryThe coronavirus disease-2019 (COVID-19), a contagious disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV2), has reached pandemic status. As it spreads across the world, it has overwhelmed healthcare systems, strangled the global economy and led to a devastating loss of life. Widespread efforts from regulators, clinicians and scientists are driving a rapid expansion of knowledge of the SARS-CoV2 virus and the COVID-19 disease.We review the most current data with a focus on our basic understanding of the mechanism(s) of disease and translation to the clinical syndrome and potential therapeutics. We discuss the basic virology, epidemiology, clinical manifestation, multi-organ consequences, and outcomes. With a focus on cardiovascular complications, we propose several mechanisms of injury. The virology and potential mechanism of injury form the basis for a discussion of potential disease-modifying therapies.

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Replication-dependent downregulation of cellular angiotensin-converting enzyme 2 protein expression by human coronavirus NL63

Cited by 134 publications

References 39 publications

Human Coronavirus NL63 Utilizes Heparan Sulfate Proteoglycans for Attachment to Target Cells

Human Coronavirus NL63 Utilizes Heparan Sulfate Proteoglycans for Attachment to Target Cells

Renin–Angiotensin–Aldosterone System Inhibitors in Patients with Covid-19

COVID-19 for the Cardiologist

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