title: ACE2 receptor expression and severe acute respiratory syndrome coronavirus infection depend on differentiation of human airway epithelia.
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.
authors.affiliation: Department of Pediatrics, 240-G EMRB, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Hong Peng
authors.initials: HP
authors.lastname: Jia
authors.forename: Dwight C
authors.initials: DC
authors.lastname: Look
authors.forename: Lei
authors.initials: L
authors.lastname: Shi
authors.forename: Melissa
authors.initials: M
authors.lastname: Hickey
authors.forename: Lecia
authors.initials: L
authors.lastname: Pewe
authors.forename: Jason
authors.initials: J
authors.lastname: Netland
authors.forename: Michael
authors.initials: M
authors.lastname: Farzan
authors.forename: Christine
authors.initials: C
authors.lastname: Wohlford-Lenane
authors.forename: Stanley
authors.initials: S
authors.lastname: Perlman
authors.forename: Paul B
authors.initials: PB
authors.lastname: McCray
mesh_terms: D000085962:Angiotensin-Converting Enzyme 2; D002268:Carboxypeptidases / Q000378:metabolism*; D002454:Cell Differentiation; D002460:Cell Line; D018352:Coronavirus Infections / Q000201:enzymology / Q000378:metabolism*; D004847:Epithelial Cells / Q000737:chemistry / Q000166:cytology* / Q000821:virology; D006801:Humans; D007703:Peptidyl-Dipeptidase A; D011991:Receptors, Virus / Q000378:metabolism*; D045473:Severe acute respiratory syndrome-related coronavirus / Q000378:metabolism*; D045169:Severe Acute Respiratory Syndrome / Q000473:pathology / Q000503:physiopathology* / Q000821:virology
chemical_list: D011991:Receptors, Virus; D002268:Carboxypeptidases; D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; D000085962:Angiotensin-Converting Enzyme 2