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Coronavirus Entry and Release in Polarized Epithelial Cells: a Review

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Coronavirus Entry and Release in Polarized Epithelial Cells: a Review See discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/261744708 Coronavirus entry and release in polarized epithelial cells: A review Article in Reviews in Medical Virology · September 2014 DOI: 10.1002/rmv.1792 · Source: PubMed CITATIONS READS 20 1,344 2 authors: Yingying Cong Xiaofeng Ren University of Groningen Northeast Agricultural University 12 PUBLICATIONS 220 CITATIONS 83 PUBLICATIONS 1,724 CITATIONS SEE PROFILE SEE PROFILE Some of the authors of this publication are also working on these related projects: Hanover Germany View project All content following this page was uploaded by Yingying Cong on 25 June 2018. The user has requested enhancement of the downloaded file. Rev. Med. Virol. 2014; 24: 308–315. Published online 16 April 2014 in Wiley Online Library (wileyonlinelibrary.com) Reviews in Medical Virology DOI: 10.1002/rmv.1792 REVIEW Coronavirus entry and release in polarized epithelial cells: a review Yingying Cong and Xiaofeng Ren* Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Northeast Agricultural University, Harbin, China SUMMARY Most coronaviruses cause respiratory or intestinal infections in their animal or human host. Hence, their interaction with polarized epithelial cells plays a critical role in the onset and outcome of infection. In this paper, we review the knowledge regarding the entry and release of coronaviruses, with particular emphasis on the severe acute respiratory syndrome and Middle East respiratory syndrome coronaviruses. As these viruses approach the epithelial surfaces from the apical side, it is not surprising that coronavirus cell receptors are exposed primarily on the apical domain of polarized epithelial cells. With respect to release, all possibilities appear to occur. Thus, most coronaviruses exit through the apical surface, several through the basolateral one, although the Middle East respiratory syndrome coronavirus appears to use both sides. These observations help us understand the local or systematic spread of the infection within its host as well as the spread of the virus within the host population. Copyright © 2014 John Wiley & Sons, Ltd. Received: 14 October 2013; Revised: 20 March 2014; Accepted: 20 March 2014 INTRODUCTION gastroenteritis virus (TGEV), porcine respiratory CoV Coronaviruses (CoVs) comprise a large family of (PRCoV) and porcine epidemic diarrhea virus enveloped, positive-stranded RNA viruses that infect (PEDV); canine CoV (CCoV), feline CoV (FCoV), a broad range of animal hosts as well as humans. bovine CoV (BCoV), human CoVs (HCoVs) including These viruses can cause a wide variety of diseases, in HCoV-229E, HCoV-OC43, HCoV-NL63 and HCoV- particular respiratory and enteric, but also including HKU1, severe acute respiratory syndrome-associated hepatic, renal and neuronal infection [1,2]. CoVs are CoV (SARS-CoV) and Middle East respiratory divided into three genera, namely, Alphacoronavirus, syndrome virus (MERS-CoV); murine hepatitis virus Betacoronavirus and Gammacoronavirus,aswellasa (MHV); and the avian CoV infectious bronchitis virus tentative new genus, the Deltacoronavirus [3]. Well- (IBV) and turkey CoV (TCoV) [4]. known representatives are porcine transmissible The CoV genome typically encodes four struc- tural proteins: the spike protein (S), envelope pro- *Correspondence author: X. Ren, Department of Preventive Veterinary tein (E), membrane protein (M) and nucleocapsid Medicine, College of Veterinary Medicine, Northeast Agricultural protein (N); some CoVs additionally have a University, 59 Mucai Street, Harbin 150030, China. haemagglutinin-esterase (HE) protein [5–7]. The S E-mail: [email protected] or [email protected] glycoprotein of CoV is the dominant surface protein Abbreviations used and is responsible for virus attachment and ACE2, angiotensin-converting enzyme II; BCoV, bovine coronavirus; membrane fusion [8–11]. Calu-3, a human lung cancer cell line; CCoV, canine coronavirus; CFR, case fatality rate; CoVs, coronaviruses; E, envelope protein; Epithelia are formed of cells that line the cavities fAPN, feline aminopeptidase-N; FCoV, feline coronavirus; HCoVs, in the body and also cover flat surfaces. Epithelial human coronaviruses; HE, haemagglutinin esterase; IBV, avian coro- cells cover the inner and outer linings of body navirus infectious bronchitis virus; IEC, intestinal epithelial cells; LLC- PK1, LLC-pig kidney 1; M, membraneprotein;MERS-CoV,MiddleEast cavities and act as a primary barrier to infection respiratory syndrome virus; MHV, murine hepatitis virus; N, nucleocapsid by microorganisms, entering their host via body protein; pAPN, porcine aminopeptidase-N; PEDV, porcine epidemic cavities, such as the respiratory or intestinal tract diarrhea virus; PRCoV,porcine respiratory coronavirus; S, spike protein; fi SARS-CoV, severe acute respiratory syndrome-associated coronavirus; [12]. Primary replication of CoVs is often con ned TCoV, turkey coronavirus; TGEV, transmissible gastroenteritis. to respiratory or gastrointestinal tract epithelial Copyright © 2014 John Wiley & Sons, Ltd. Polarized infection of coronaviruses 309 cells [13]. Epithelial cells are functionally polarized; epithelial in relation to CoV entry is important for their surface exhibits two distinguishable regions, understanding virus invasion. It is well known that which are called apical domain and basolateral porcine aminopeptidase-N (pAPN), the cellular domain [14]. The apical membrane faces the lumi- receptor of TGEV, is primarily expressed on the nal (external) compartment and contains proteins apical side in polarized epithelial cells [18,30]. that determine the cells’ primary functions such as Rossen et al. chose LLC-PK1 cells, which are secretion and absorption, whereas the basolateral derived from the proximal tubule of porcine domain faces the systemic (internal) compartment, kidney, as their in vitro model for determining the that is, tissues and blood [15,16]. association of TGEV entry with localization of As CoVs generally spread through the fecal–oral pAPN [18]. Furthermore, the authors performed a or respiratory route, polarized epithelial cells confocal laser scanning microscope method of constitute their first natural barrier. Hence, their filter-grown LLC-PK1 cells, which allows optical interaction with these cells determines for a major sections to be cut either in the horizontal plane part the outcome of the infection [17]. In this paper, (XY section) or in the vertical plane (XZ section) we review the entry and release of several CoVs in to determine the plasma membrane distribution of polarized epithelial cells as this information will the pAPN receptor. The results showed that when contribute to our understanding of the pathogene- the LLC-PK1 cells were not fully polarized, pAPN sis of these viruses. was expressed on both apical and basolateral sides; in contrast, expression of the pAPN was limited to CORONAVIRUS ENTRY INTO POLARIZED the apical side in fully polarized LLC-PK1 mono- EPITHELIAL CELLS layers [18], consistent with TGEV entry into these The entry of several CoVs in polarized epithelial cells to be mediated by pAPN. Similarly, also the cells has been investigated for several decades. As entry of HCoV-229E and FCoV through the apical early as 1994, Rossen and colleagues analyzed the domain of polarized epithelial cells correlated with entry of TGEV in filter-grown polarized LLC-pig the apical expression of their cognate aminopepti- kidney 1 (LLC-PK1) cells, a line of pig kidney dase-N (APN) receptor [19,20,24,31–34]. Besides, epithelial cells, using radioactive labeling, immu- the apical distribution of angiotensin-converting noprecipitation and electron microscopy. The enzyme II (ACE2; HCoV-NL63 receptor) mediated results showed that TGEV infection was restricted the apical entry of HCoV-NL63 [24,26]. For their to the apical plasma membrane [18]. In 2001, study of polarized MHV entry, Rossen et al. used Rossen et al. similarly analyzed the entry of FCoV porcine LLC-PK1 cells stably expressing the and CCoV in polarized epithelial LLC-PK1 cells ex- carcinoembryonic antigen receptor for MHV pressing the recombinant feline aminopeptidase-N (MHVR) and confirmed that the apical entry of (fAPN), which acts as a receptor for these viruses, the virus could be explained by the specific apical and compared it with TGEV. The results showed expression of its receptor [23,35]. As far as the entry that FCoV and CCoV, like TGEV, establish their of SARS-CoV is concerned, Tseng et al. first infection into polarized epithelial cells specifically reported the apical entry of this virus in polarized by entry through the apical membrane [19]. The Calu-3 (a human lung cancer cell line) cells in same pattern has subsequently also been found with 2005 using immunofluorescence staining, confocal a large number of other CoVs including HCoV- microscopy and transmission electron microscopy 229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, BCoV, [17]. In the same year, Jia et al. investigated interac- SARS-CoV and MHV [4,17,18,20–28]. Recently, tions between SARS-CoV and human airway Pratelli reported a study with CCoV in filter-grown epithelia using native tissue and a primary culture polarized epithelia primary dog kidney cells (A72 model of polarized, well-differentiated tracheal cells) and epithelia feline kidney cells (CrFK cells) and bronchial epithelia [21]. They also confirmed showing productive infection both through the SARS-CoV receptor, ACE2, to be expressed in apical and basolateral
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