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1、OPINION Coronavirus infection of polarized epithelial cells John W.A. Rossen, Marian C. Horzinek and Peter J.M. Rottier E pithelial cells form highly organized sheets that line the body cavities of higher eu- karyotes and are the first barrier against infection. Their plasma membranes are organized
2、to form an apical face, directed towards the external milieu, and a basolateral face, oriented towards the internal environment. Tight junctions with neighbouring cells separate the two faces and not only confine their components, but also restrict inter- cellular diffusion. Viruses can enter epithe
3、lial cells or be released from them through either membrane face (for a review, see Ref. 1). Polarized virus entry is often a result of the polarized dis- tribution of the viral receptor, as shown for vesicular stomatitis virus and simian virus 40 (Ref. 1). The presence of the receptor only on the b
4、asolateral surface significantly hinders infection. Although not the only determinant, polarized virus release can influence viral spread. Basolateral release allows the infec- tion of underlying tissues and the spread of virus in the blood leading to systemic infection, while apical release from ep
5、ithelial cells can limit viral spread by preventing the in- fection of other cell types. For ex- ample, parainfluenza viruses, which cause a localized infection of the respiratory tract in humans, are re- leased by budding through the api- cal membrane2 Similarly, Sendai virus, which is exclusively
6、pneumo- tropic in mice, also buds from the apical surface of epithelial cells, while a mutant Sendai virus that could infect multiple cell types was found to bud through both the api- cal and basolateral faces3 Corona viruses are enveloped, positive-strand RNA viruses in- fecting humans, animals and
7、 birds. While each virus has a narrow host range, the consequences of infection range from subclinical to lethal, and Epithelial cells are the first host cells to be infected by incoming coronaviruses. Recent observations in vitro show that coronaviruses are released from a specific side of these po
8、larized cells, and this polarized release might be important for the spread of the infection ill vivo. Mechanisms for the directional sorting of coronaviruses might be similar to those governing the polar release of secretory proteins. J. v.A. Rossen, M.e. Horzillek alld P.J.M Rattier are in the Vir
9、ology Divn of the Dept of Infectiolls Diseases and Immllnolog, FaCIlIty of Veterinary Medicine, Utrecht University, Yalelaall 1, 3584 CL Utrecht, The Netherlands. tel: +31302532485, fax: +31302536723, email: P.Rottiervetl1lic.dgk.TllII.nl symptoms include respiratory and enteric disease (most common
10、ly), as well as hepatitis, peritonitis and encephalomyelitis4 HOvever, pri- mary replication is often limited to epithelial cells of the respiratory or gastrointestinal tracts (Table 1). A better insight into the interaction of coronaviruses with these cells is important for understanding their path
11、ogenesis. This article summa- rizes current knowledge and pre- sents recent results from our studies ill vitro. Coronavirus infection of epithelia Coronaviruses are assembled in the intermediate or budding compart- ment5,6, which is located between the rough endoplasmic reticulum and the Golgi compl
12、ex. The viral particles are transported in vesicles through the secretory pathway to the plasma membrane, where they are released by exocytosis7 Virions can also be released by lysis of dying cells. Obviously, directional release is significant to coronavirus patho- CD 1995 Elsevier Science Ltd 0966
13、842XJ95/S09.50 genesis only when the epithelial layer stays intact. Although infected cells are extruded from the epithelial layer and replaced by new ones8-12, it is only after excessive cell loss that the monolayer disintegrates13 In neonates, the replacement of (infected) epithelial cells is slow
14、er and more cells are infected than in adults; consequently, epithelial lesions are more severeI4,15. This is consistent with the observation that neonates are often fully suscep- tible to a corona virus that does not affect older animals4,14-17. Age- dependent sensitivity to a virus can also be det
15、ermined by other factors. For example, a receptor protein for transmissible gastroenteritis virus (TGEV) that is restricted to the vil- lous enterocytes of newborn animals has been found recentlyl5. Another factor that may contribute to the high sensitivity of neonates is the lack of natural killer
16、activity in their intraepitheliallymphocytesl5 Release of mouse hepatitis virus (MHV) in vivo MHV is the best-studied corona- virus. It has many strains, which dif- fer in tropism. Viruses of the entero- tropic biotype (such as MHV-Y) infect the intestinal mucosa, with little infection of other tissues (see Ref. 17 and references contained). Infection of 2-3 week old mice results in mild intestinal lesions with minimal alteration of the mu- cosal architecture, and the virus does not spre
