Coronavirus (CoV) infection of humans is usually not associated with severe disease. However, discovery of the severe acute respiratory syndrome (SARS) CoV revealed that highly pathogenic human CoVs (HCoVs) can evolve. The identification and characterization of new HCoVs is, therefore, an important task. Recently, a HCoV termed NL63 was discovered in patients with respiratory tract illness. Here, cell tropism and receptor usage of HCoV-NL63 were analyzed. The NL63 spike (S) protein mediated infection of different target cells compared with the closely related 229E-S protein but facilitated entry into cells known to be permissive to SARS-CoV-S-driven infection. An analysis of receptor engagement revealed that NL63-S binds angiotensin-converting enzyme (ACE) 2, the receptor for SARS-CoV, and HCoV-NL63 uses ACE2 as a receptor for infection of target cells. Potent neutralizing activity directed against NL63-but not 229E-S protein was detected in virtually all sera from patients 8 years of age or older, suggesting that HCoV-NL63 infection of humans is common and usually acquired during childhood. Here, we show that SARS-CoV shares its receptor ACE2 with HCoV-NL63. Because the two viruses differ dramatically in their ability to induce disease, analysis of HCoV-NL63 might unravel pathogenicity factors in SARS-CoV. The frequent HCoV-NL63 infection of humans suggests that highly pathogenic variants have ample opportunity to evolve, underlining the need for vaccines against HCoVs.C oronaviruses (CoVs) are enveloped RNA viruses that are grouped according to genome sequence and serology (1). Human CoVs (HCoVs) 229E and OC43 are members of groups I and II, respectively, and infection with these viruses is thought to be responsible for Ϸ30% of common-cold cases (1). In contrast, infection with severe acute respiratory syndrome (SARS)-CoV causes a severe respiratory tract illness (RTI) that is fatal in Ϸ10% of infected individuals (2, 3). The factors that determine the pathogenicity of CoVs are incompletely understood; however, a role for the spike (S) protein has been suggested (4). The S proteins of CoVs, which provide virions with a corona-like appearance, mediate infection of target cells and play a central role in viral replication (4). The interaction of CoV S proteins with specific cellular receptors determines, to a large extent, which cells can be infected (5), and the entry process is an attractive target for antiviral therapy (6).Recently, a HCoV termed NL63 was discovered in infants and immunocompromised adults with RTI (7, 8). HCoV-NL63 is a group I CoV and is most closely related to HCoV-229E (7-9). HCoV-229E employs CD13 (aminopeptidase N) as a receptor for infection of target cells (10,11). Because the NL63-and 229E-S proteins share 56% amino acid identity (7), it is conceivable that HCoV-NL63 also engages CD13 for infectious cellular entry. However, the HCoV-NL63-S protein contains a unique, 179-aa sequence at its N terminus that does not share homology with other known CoV proteins and that might alter the re...

The lectins DC-SIGN and DC-SIGNR can augment viral infection; however, the range of pathogens interacting with these attachment factors is incompletely defined. Here we show that DC-SIGN and DC-SIGNR enhance infection mediated by the glycoprotein (GP) of Marburg virus (MARV) and the S protein of severe acute respiratory syndrome coronavirus and might promote viral dissemination. SIGNR1, a murine DC-SIGN homologue, also enhanced infection driven by MARV and Ebola virus GP and could be targeted to assess the role of attachment factors in filovirus infection in vivo.

The angiotensin converting enzyme 2 (ACE2) has been identified as a receptor for the severe acute respiratory syndrome associated coronavirus (SARS-CoV). Here we show that ACE2 expression on cell lines correlates with susceptibility to SARS-CoV S-driven infection, suggesting that ACE2 is a major receptor for SARS-CoV. The soluble ectodomain of ACE2 specifically abrogated S-mediated infection and might therefore be exploited for the generation of inhibitors. Deletion of a major portion of the cytoplasmic domain of ACE2 had no effect on S-driven infection, indicating that this domain is not important for receptor function. Our results point to a central role of ACE2 in SARS-CoV infection and suggest a minor contribution of the cytoplasmic domain to receptor function.