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Severe acute respiratory syndrome (SARS) is caused by a novel coronavirus called SARS-CoV (1-3). The virus causes atypical pneumonia with diffuse alveolar damage with an overall mortality of Ϸ10% that ranges from 0% in children and 50% in persons over 65 (2). Coronaviruses bind to their glycoprotein receptors by the Ϸ200-kDa spike glycoprotein, S, on the viral envelope. Identification of virus receptors can provide insight into mechanisms of virus entry, tissue tropism, pathogenesis, and host range.Several types of receptors were previously identified for coronavirus S glycoproteins. The receptors for the murine coronavirus mouse hepatitis virus are murine carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1) and related murine glycoproteins in the carcinoembryonic antigen family in the Ig superfamily (4). The receptors for human coronavirus 229E (HCoV-229E), transmissible gastroenteritis virus of swine, and feline coronavirus in genetic group 1 are aminopeptidase N (APN) glycoproteins (5-8).Angiotensin-converting enzyme 2 (ACE2) was found to be an efficient receptor for the S glycoprotein of SARS-CoV (9, 10). Because the Vero line of rhesus monkey kidney cells is highly susceptible to infection with SARS-CoV, Li et al. (9) used a codon-optimized soluble SARS-CoV spike glycoprotein (amino acids 12-672) fused to the Fc domain of human IgG1 to immunoprecipitate a putative receptor glycoprotein from Vero cell membranes and identified the simian ACE2 protein by mass spectrometry. They showed that expression of recombinant human ACE2 greatly enhanced the susceptibility of human 293T cells to infection by SARS-CoV. Wang et al. (10) independently demonstrated that human ACE2 is a receptor for SARS-CoV by transducing HeLa cells with a retrovirus library of cDNAs from Vero E6 cells and by using flow cytometry to select transduced cells that bound to purified soluble SARS-CoV S glycoprotein (amino acids 14-502) with a 6-histidine tag. They found that the simian cDNA in these cells, which encoded triosephosphate isomerase, enhanced expression of human ACE2 by inserting into the HeLa cell genome immediately upstream of the ACE2 ORF. Murine NIH 3T3 cells expressing recombinant human ACE2, but not those expressing recombinant triosephosphate isomerase, were susceptible to infection by HIV pseudovirus expressing SARS-CoV S protein.In this report, we describe the discovery of an additional receptor for SARS-CoV, CD209L (also called L-SIGN, DC-SIGNR, and DC-SIGN2) (11). Our strategy for identifying a SARS-CoV receptor was to transduce a human lung cDNA library carried by a retroviral vector into Chinese hamster ovary (CHO) cells and use flow cytometry to select transduced CHO cells that bound soluble, codon-optimized, c-myc-tagged SARSCoV S 590 glycoprotein (amino acids 1-590) expressed in 293T cells. The SARS-CoV S 590 -binding cells were then challenged with infectious SARS-CoV, and infection was demonstrated by detection of subgenomic viral RNA synthesis and immunofluorescence with antiviral antibody. The finding that ...

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