Only a relatively few mutations in its spike protein allow the murine coronavirus to switch from a murinerestricted tropism to an extended host range by being passaged in vitro. One such virus that we studied had acquired two putative heparan sulfate-binding sites while preserving another site in the furin-cleavage motif. The adaptation of the virus through the use of heparan sulfate as an attachment/entry receptor was demonstrated by increased heparin binding as well as by inhibition of infection through treatment of cells and the virus with heparinase and heparin, respectively.Coronaviruses are enveloped, plus-stranded RNA viruses, which generally cause respiratory and/or intestinal infections, although some may spread systemically. They are pathogens of veterinary importance, often associated with great economic losses. Their relevance has increased considerably since the recent emergence of new human coronaviruses (HCoV), such as the severe acute respiratory syndrome coronavirus (SARSCoV). In general, coronaviruses have a limited host range and cause disease in a single or a few closely related host species. However, the emergence of SARS-CoV, which resulted from a zoonotic transmission event (19), demonstrates the need for a better understanding of coronavirus interspecies transmission.The interaction of the coronavirus spike (S) protein, a class I fusion protein (5), with its receptor is the major determinant for virus entry and host range restriction. While nonpermissive cell lines can be rendered susceptible by making them express the receptor (see references below), coronaviruses can also be retargeted to specific cells by exchanging the ectodomain of the S protein with that of another appropriate coronavirus, as was demonstrated for mouse hepatitis virus (MHV) (24) and feline infectious peritonitis virus (20). Receptors have so far been identified for the group 2 coronavirus MHV (murine carcinoembryonic antigen-related cell adhesion molecule 1 [CEACAM1]) (16, 38), for SARS-CoV (ACE2) (26), for the group 1 coronaviruses transmissible gastroenteritis virus and porcine respiratory coronavirus (porcine APN) (12, 13), for feline infectious peritonitis virus (feline APN) (36), for HCoV-229E (human APN) (40), and for HCoV-NL63 (ACE2) (21).The S protein is synthesized as a heavily glycosylated polypeptide, which oligomerizes in the endoplasmic reticulum to form trimers (14, 27). As a late maturation step during its transport to the cell surface, cleavage of the MHV S protein into an amino-terminal S1 and a carboxy-terminal S2 domain can occur. A basic amino acid sequence resembling the furin consensus sequence motif occurs approximately in the middle of the protein and was shown to be the target of a furin-like enzyme in the case of MHV-A59 (11). While cleavage of the MHV S protein generally correlates strongly with cell-cell fusion (7), virus-cell fusion appears not to be affected by the prevention of S protein cleavage, indicating that these fusion events have different requirements (11).The amino-terminal S...
The entry of enveloped viruses into cells requires attachment of the virion to the host cell, followed by fusion of the viral membrane with a membrane of the target cell. While some viruses contain glycoproteins that mediate both virus-cell attachment and virus-cell fusion, as is the case for coronaviruses, for others, such as paramyxoviruses, these functions are served by different glycoproteins. In both cases, however, the viral fusion proteins undergo dramatic conformational changes upon activation, which are tightly controlled in time and place in order to effect the proper merging of viral and cellular membranes.Coronaviruses are enveloped viruses that contain a large single-stranded RNA genome of positive polarity. Their envelope accommodates three or four membrane proteins of which the membrane (M), envelope (E), and spike (S) proteins are common to all (reviewed by de Haan and Rottier [15]). The S protein is a relatively large, 1160-to 1452-amino-acid-long type I glycoprotein, trimers of which form the petal-shaped projections on the surface of the virion that give rise to the characteristic corona solis-like appearance. The S proteins from some but not all coronaviruses are cleaved as a late step during their maturation (reviewed by Cavanagh [8]), for which a furin-like enzyme was shown to be responsible in the case of mouse hepatitis virus (MHV) strain A59 (16). The resulting aminoterminal S1 subunit and the membrane-anchored S2 subunit remain noncovalently linked. It has been suggested that the S1 subunit constitutes the globular head, while the S2 subunit forms the stalk-like region of the spike (8, 9).The two functions of the coronavirus S protein appear to be spatially separated. The S1 subunit (or the equivalent part in viruses with uncleaved S protein) is responsible for receptor binding, and the S2 subunit is responsible for membrane fusion. For MHV, the receptor-binding domain has been mapped to the amino-terminal 330 residues of the S molecule (23, 42). For transmissible gastroenteritis virus (20), human coronavirus 229E (4, 7), and severe acute respiratory syndrome (SARS) coronavirus (1, 44), the receptor-binding domains have also been mapped to the S1 subunit, though to different regions therein. The ectodomain of the S2 subunit contains two heptad repeat (HR) regions (9) (Fig. 1), characteristic of coiled coils, while the fusion peptide (FP) is predicted to be located amino terminally of the first HR region (HR1) (5). Binding of the S1 subunit to the (soluble) receptor has been shown to trigger conformational changes that supposedly fa-
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