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

Jia, Hong Peng; Look, Dwight C.; Shi, Lei; Hickey, Melissa; Pewe, Lecia; Netland, Jason; Farzan, Michael; Wohlford‐Lenane, Christine L.; Perlman, Stanley; McCray, Paul B.

doi:10.1128/jvi.79.23.14614-14621.2005

Cited by 885 publications

(911 citation statements)

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“…Tissue expression of the receptor correlates with the localization of the virus in infected individuals and animals. 22,47,61,62 In addition, the efficiency of infection is correlated with the ability of the ACE2 within each species to support viral replication. A study of ACE2 knockout mice indicated that the enzyme is a crucial receptor for SARS-CoV in vivo 24 and that SARS-CoV and the S protein both reduce ACE2 expression.…”

Section: Role Of Ace2 In the Pathogenesis Of Sarsmentioning

confidence: 99%

Studies of Severe Acute Respiratory Syndrome Coronavirus Pathology in Human Cases and Animal Models

2010

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During the severe acute respiratory syndrome (SARS) outbreak of 2003, approximately 10% of SARS patients developed progressive respiratory failure and died. Since then, several animal models have been established to study SARS coronavirus, with the aim of developing new antiviral agents and vaccines. This short review describes the pathologic features of SARS in relation to their clinical presentation in human cases. It also looks at animal susceptibility after experimental infection, animal models of SARS, and the pathogenesis of this disease. It seems that adaptation of the virus within the host animal and the subsequent abnormal immune responses may be key factors in the pathogenesis of this new and fatal respiratory disease. The proteases produced in the lung during inflammation could also play an important role for exacerbation of SARS in animals.

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Section: Role Of Ace2 In the Pathogenesis Of Sarsmentioning

confidence: 99%

Studies of Severe Acute Respiratory Syndrome Coronavirus Pathology in Human Cases and Animal Models

2010

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“…ACE2 is predominantly expressed on the apical surface of well-differentiated airway epithelia, especially ciliated cells (30,56). Since a virus must attach to and enter cells before it can replicate, surface expression of ACE2 and the state of cell differentiation may directly influence SARS-CoV disease pathogenesis (30).…”

mentioning

confidence: 99%

Ectodomain shedding of angiotensin converting enzyme 2 in human airway epithelia

Jia¹,

Look²,

Tan³

et al. 2009

American Journal of Physiology-Lung Cellular and Molecular Phys

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308

403

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verting enzyme 2 (ACE2) is a terminal carboxypeptidase and the receptor for the SARS and NL63 coronaviruses (CoV). Loss of ACE2 function is implicated in severe acute respiratory syndrome (SARS) pathogenesis, but little is known about ACE2 biogenesis and activity in the airways. We report that ACE2 is shed from human airway epithelia, a site of SARS-CoV infection. The regulation of ACE2 release was investigated in polarized human airway epithelia. Constitutive generation of soluble ACE2 was inhibited by DPC 333, implicating a disintegrin and metalloprotease 17 (ADAM17). Phorbol ester, ionomycin, endotoxin, and IL-1␤ and TNF␣ acutely induced ACE2 release, further supporting that ADAM17 and ADAM10 regulate ACE2 cleavage. Soluble ACE2 was enzymatically active and partially inhibited virus entry into target cells. We determined that the ACE2 cleavage site resides between amino acid 716 and the putative transmembrane domain starting at amino acid 741. To reveal structural determinants underlying ACE2 release, several mutant and chimeric ACE2 proteins were engineered. Neither the juxtamembrane stalk region, transmembrane domain, nor the cytosolic domain was needed for constitutive ACE2 release. Interestingly, a point mutation in the ACE2 ectodomain, L584A, markedly attenuated shedding. The resultant ACE2-L584A mutant trafficked to the cell membrane and facilitated SARS-CoV entry into target cells, suggesting that the ACE2 ectodomain regulates its release and that residue L584 might be part of a putative sheddase "recognition motif." Thus ACE2 must be cell associated to serve as a CoV receptor and soluble ACE2 might play a role in modifying inflammatory processes at the airway mucosal surface. a disintegrin and metalloprotease 17; severe acute respiratory syndrome; coronavirus SEVERE ACUTE RESPIRATORY SYNDROME (SARS) emerged as a regional and global health threat in 2002-2003 resulting in ϳ8,000 cases and 800 deaths. The causative agent was identified as a novel human coronavirus Refs. 8,33,51). Studies (13,47) of patients with SARS demonstrated that the respiratory tract is a major site of SARS-CoV infection and disease-associated morbidity. In 2003, angiotensin-converting enzyme 2 (ACE2) was discovered as a receptor for the virus (39). ACE2 is expressed in vascular endothelia, lung, renal and cardiovascular tissues, testes, and epithelia of the small intestine (9,17,18). It is a terminal carboxypeptidase that cleaves a single residue from ANG II, generating ANG-(1-7) (10, 32, 60). In addition, ACE2 cleaves the terminal residues from several other bioactive peptides, including neurotensin, dynorphin A (1-13), apelin-13, and des-Arg bradykinin (9, 60). As a type I transmembrane protein, ACE2 is comprised of a short cytoplasmic domain, a transmembrane domain, and a large ectodomain (57). A region of the ACE2 ectodomain that includes the first ␣-helix and lysine 353 and proximal residues of the N-terminus of ␤-sheet 5 interacts with high affinity with the receptor-binding domain of the SARS-CoV S glycoprotein (40).Previ...

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“…Viral infectivity of airway epithelia is often polarized and correlates with differential expression of corresponding viral receptors. For example, 229E and severe acute respiratory syndrome coronaviruses infect human airway epithelia at higher efficiency from the apical surface, and this correlates with predominant apical expression of their receptors, aminopeptidase N (CD13) and angiotensin-converting enzyme 2 (15,33). In contrast, adenoviruses infect human airway epithelia best from the basolateral surface, which correlates with Coxsackie virus and adenovirus receptor segregation to the basolateral surface (34).…”

Section: Discussionmentioning

confidence: 99%

“…The basolateral or apical surfaces of airway epithelia were selectively treated with 1 mg/ml N-hydroxysulfosuccinimidobiotin (Pierce) in PBS for 30 min at 25°C as described previously (15). The epithelial surface was washed and then incubated with 100 mM glycine in PBS for 20 min at 25°C to quench unreacted biotin.…”

Section: Surface Protein Isolationmentioning

confidence: 99%

“…These cells were grown as epithelia by plating at a density of 5 ϫ 10 5 cells/cm 2 onto 0.6-cm 2 , collagencoated, semipermeable, polycarbonate membranes (Millipore). Epithelial cells under these culture conditions were grown in 49% DMEM, 49% Ham's F12 medium, 2% Ultroser G (Sepracor), 100 U/ml penicillin G, 100 g/ml streptomycin, 50 g/ml gentamicin, 2 g/ml fluconazole, and 1.25 g/ml amphotericin B as described previously (11)(12)(13)(14)(15). Medium was removed from the apical chamber 24 h after plating to establish air-liquid interface culture conditions, and basolateral culture medium was changed every 2-4 days.…”

Section: Airway Epithelial Cell Isolation Culture and Treatmentsmentioning

confidence: 99%

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Paracellular Permeability Restricts Airway Epithelial Responses to Selectively Allow Activation by Mediators at the Basolateral Surface

Humlicek

Manzel

Chin

et al. 2007

The Journal of Immunology

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Respiratory pathogens and toxins often assault the lung from the airway lumen. Airway epithelia may initiate and amplify inflammation in response to these attacks, but under certain conditions confinement of inflammation to the airway lumen may be beneficial to the host. Accordingly, we hypothesized that airway epithelial polarity allows different responses to basolateral vs apical stimuli that may modulate inflammation. Using primary human airway epithelial cells differentiated at an air-liquid interface in culture, we found that responses to several cytokines required basolateral mediator application. In contrast, responses to Haemophilus influenzae occurred after either basolateral or apical interaction with airway epithelia. Experiments focused on IFN-γ receptor polarity confirmed its predominant basolateral location in cultured airway epithelia as well as in normal human airway tissue. Furthermore, physical and pharmacologic disruption of barrier function in airway epithelia allowed responses to apical application of IFN-γ and other cytokines. These in vitro studies directly correlated with experiments in mice in which an airway epithelial response to IFN-γ injected into the airway lumen was seen only after disruption of barrier function. The results indicate that airway epithelia with intact barrier function restrict inflammatory responses by limitation of cell activation through requiring interaction of selected mediators with the basolateral surface. However, loss of barrier integrity allows epithelial responses to these mediators if located in the airway lumen to amplify airway defenses.

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

Cited by 885 publications

References 50 publications

Studies of Severe Acute Respiratory Syndrome Coronavirus Pathology in Human Cases and Animal Models

Studies of Severe Acute Respiratory Syndrome Coronavirus Pathology in Human Cases and Animal Models

Ectodomain shedding of angiotensin converting enzyme 2 in human airway epithelia

Paracellular Permeability Restricts Airway Epithelial Responses to Selectively Allow Activation by Mediators at the Basolateral Surface

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