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J Virol. 2005 Dec; 79(23): 14614–14621.

doi: 10.1128/JVI.79.23.14614-14621.2005

PMCID: PMC1287568

PMID: 16282461

ACE2 Receptor Expression and Severe Acute Respiratory Syndrome Coronavirus Infection Depend on Differentiation of Human Airway Epithelia

Hong Peng Jia,¹ Dwight C. Look,² Lei Shi,² Melissa Hickey,¹ Lecia Pewe,¹ Jason Netland,¹ Michael Farzan,³ Christine Wohlford-Lenane,¹ Stanley Perlman,¹ and Paul B. McCray, Jr^1,*

Hong Peng Jia

Departments of Pediatrics,¹ Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242,² Department of Microbiology and Molecular Genetics, Harvard University, Cambridge, Massachusetts 02138³

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Dwight C. Look

Departments of Pediatrics,¹ Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242,² Department of Microbiology and Molecular Genetics, Harvard University, Cambridge, Massachusetts 02138³

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Lei Shi

Departments of Pediatrics,¹ Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242,² Department of Microbiology and Molecular Genetics, Harvard University, Cambridge, Massachusetts 02138³

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Melissa Hickey

Departments of Pediatrics,¹ Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242,² Department of Microbiology and Molecular Genetics, Harvard University, Cambridge, Massachusetts 02138³

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Lecia Pewe

Departments of Pediatrics,¹ Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242,² Department of Microbiology and Molecular Genetics, Harvard University, Cambridge, Massachusetts 02138³

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Jason Netland

Departments of Pediatrics,¹ Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242,² Department of Microbiology and Molecular Genetics, Harvard University, Cambridge, Massachusetts 02138³

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Michael Farzan

Departments of Pediatrics,¹ Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242,² Department of Microbiology and Molecular Genetics, Harvard University, Cambridge, Massachusetts 02138³

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Christine Wohlford-Lenane

Departments of Pediatrics,¹ Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242,² Department of Microbiology and Molecular Genetics, Harvard University, Cambridge, Massachusetts 02138³

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Stanley Perlman

Departments of Pediatrics,¹ Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242,² Department of Microbiology and Molecular Genetics, Harvard University, Cambridge, Massachusetts 02138³

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Paul B. McCray, Jr

Departments of Pediatrics,¹ Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242,² Department of Microbiology and Molecular Genetics, Harvard University, Cambridge, Massachusetts 02138³

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Author information Article notes Copyright and License information Disclaimer

Departments of Pediatrics,¹ Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242,² Department of Microbiology and Molecular Genetics, Harvard University, Cambridge, Massachusetts 02138³

^*Corresponding author. Mailing address: Department of Pediatrics, 240-G EMRB, Carver College of Medicine, University of Iowa, Iowa City, IA 52242. Phone: [phone]. Fax: [phone]. E-mail: ude.awoiu@yarccm-luap.

Received 2005 Jun 16; Accepted 2005 Sep 14.

Copyright © 2005, American Society for Microbiology

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Abstract

Studies of patients with severe acute respiratory syndrome (SARS) demonstrate that the respiratory tract is a major site of SARS-coronavirus (CoV) infection and disease morbidity. We studied host-pathogen interactions using native lung tissue and a model of well-differentiated cultures of primary human airway epithelia. Angiotensin converting enzyme 2 (ACE2), the receptor for both the SARS-CoV and the related human respiratory coronavirus NL63, was expressed in human airway epithelia as well as lung parenchyma. As assessed by immunofluorescence staining and membrane biotinylation, ACE2 protein was more abundantly expressed on the apical than the basolateral surface of polarized airway epithelia. Interestingly, ACE2 expression positively correlated with the differentiation state of epithelia. Undifferentiated cells expressing little ACE2 were poorly infected with SARS-CoV, while well-differentiated cells expressing more ACE2 were readily infected. Expression of ACE2 in poorly differentiated epithelia facilitated SARS spike (S) protein-pseudotyped virus entry. Consistent with the expression pattern of ACE2, the entry of SARS-CoV or a lentivirus pseudotyped with SARS-CoV S protein in differentiated epithelia was more efficient when applied to the apical surface. Furthermore, SARS-CoV replicated in polarized epithelia and preferentially exited via the apical surface. The results indicate that infection of human airway epithelia by SARS coronavirus correlates with the state of cell differentiation and ACE2 expression and localization. These findings have implications for understanding disease pathogenesis associated with SARS-CoV and NL63 infections.