Severe acute respiratory syndrome (SARS) is caused by infection of a previously undescribed coronavirus (CoV). L-SIGN, encoded by CLEC4M (also known as CD209L), is a SARS-CoV binding receptor that has polymorphism in its extracellular neck region encoded by the tandem repeat domain in exon 4. Our genetic risk association study shows that individuals homozygous for CLEC4M tandem repeats are less susceptible to SARS infection. L-SIGN is expressed in both non-SARS and SARS-CoV–infected lung. Compared with cells heterozygous for L-SIGN, cells homozygous for L-SIGN show higher binding capacity for SARS-CoV, higher proteasome-dependent viral degradation and a lower capacity for trans infection. Thus, homozygosity for L-SIGN plays a protective role during SARS infection.
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We are indebted to L.-C. Tsui and P. Sham for their advice and support. We thank K.F. To and P. Beh for providing autopsy materials of patients fatally infected with SARS. We thank L.Y.C. Yam, S.T. Lai, C.M. Chu, T.Y. Wong, E. Chow, E.S.K. Ma, E.Y.T. Chan, R.Y.L. Chen and M.M. Garcia-Barcelo for sample collection and C. Wong, J. Chan, W. Liu and W.C. Xue for their technical support. This project was funded by the SARS Research Fund from the University of Hong Kong, the European Research Project SARS-DTV, the US National Institute of Allergy and Infectious Diseases, the Research Fund for the Control of Infectious Diseases of Hong Kong and the Research Grant Council, HKSAR, China.
The authors declare no competing financial interests.
Reduction of the total SARS-CoV ORF-1b copy numbers is not due to viral dissociation from L-SIGN. (PDF 90 kb)
A549 cells do not express ACE2 and L-SIGN, and SARS-CoV binding to L-SIGN-transfected A549 cells also underwent degradation over time. (PDF 179 kb)
L-SIGN delivered SARS-CoV to Vero E6 cells in trans, but no difference was noted among N7, N7/N5 and N5 L-SIGN transfectants after 48 h incubation. (PDF 101 kb)
L-SIGN expressed in ACE2-transfected CHO cells or in ACE2-trasnfected A549 cells did not facilitate cis infection of SARS-CoV. (PDF 153 kb)
48 h supernatant from SARS-CoV infected N7 L-SIGN/Vero E6 cells contained a lower number of infectious virions than that from the infected N7/N5 L-SIGN/Vero E6 cultures. (PDF 98 kb)
Co-cultures of stable clones of homozygous L-SIGN/CHO cells with Vero E6 cells in a closed infection system resulted in a reduced final SARS-CoV titer. (PDF 231 kb)
CD68bright cells did not express SARS-CoV mRNA in fatal SARS lung. (PDF 138 kb)
Genotype and allele frequencies of CLEC4M (L-SIGN) in Chinese random controls and Caucasians of European descent (CEPH). (PDF 90 kb)
List of primers used. (PDF 72 kb)
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