Introduction
Severe acute respiratory syndrome (SARS) is characterized by an acute respiratory disease, often accompanied by gastroenteritis, which is fatal in approximately 10% of infected individuals (Gu and Korteweg 2007). The etiological agent is a novel coronavirus (CoV), designated as SARS-CoV, which emerged from an animal reservoir during the winter 2002–2003 when it infected over 8000 humans worldwide. It emerged again the next winter and since then, no SARS outbreak has been recorded (Chen and Subbarao 2007). Yet, a serious possibility of reemergence of SARS-CoV or of the introduction of other related viruses from an animal reservoir remains.
Spike (S) proteins of coronaviruses are large transmembrane heavily N-glycosylated proteins that mediate association with a cell surface receptor (Li et al. 2006). The SARS-CoV S protein possesses 23 N-linked glycosylation sites distributed in three clusters. The glycosylation of 13 of these sites has been confirmed (Krokhin et al. 2003; Ying et al. 2004; Chakraborti et al. 2005). Receptor binding domains (RBDs) have been identified in the S1 domain of a number of coronaviruses, and a fragment of the SARS-CoV S1 domain, from residues 318–510, binds human angiotensin-converting enzyme 2 (ACE2) with high affinity (Xiao et al. 2003; Babcock et al. 2004; Wong et al. 2004). It has additionally been demonstrated that ACE2 constitutes an obligate cellular receptor although other receptors may participate in the infection process (Li et al. 2003; Chen and Subbarao 2007). The structure of SARS-CoV RBD complexed with ACE2 revealed that an extended loop of the RBD, comprising residues 424–494, is in direct contact with ACE2 (Li et al. 2005). This receptor binding motif (RBM) is not glycosylated, but it is surrounded by two clusters of glycosylation sites (Han et al. 2007).
Various genetic factors influencing the susceptibility to or the outcome of SARS have been described (Gu and Korteweg 2007). The ABO gene stands out among the genes involved since O blood group individuals were shown to have very low odds of infection compared to non-O individuals in a hospital outbreak that occurred in March 2003 in Hong Kong (Cheng et al. 2005). Histo-blood group antigens are present not only on erythrocytes but also on many epithelial cells, which are their main site of expression (Marionneau et al. 2001). Since SARS-CoV replicates in epithelial cells of the respiratory and digestive tracts that have the ability to synthesize ABH carbohydrate epitopes, we hypothesized that the S protein of virions produced by either A or B individuals could be decorated with A or B carbohydrate epitopes, respectively. Natural anti-A or -B antibodies from blood group O, B, and A individuals could bind to the S protein and block its interaction with ACE2, thereby preventing infection in accordance with the rules of transfusion.
In order to put this hypothesis to the test, we used a cell binding assay that reconstitutes the interaction between the S protein and ACE2 (Chou et al. 2005). We present data indicating that the S protein/ACE2-mediated adhesion between cells expressing ACE2 and cells coexpressing the S protein and the A histo-blood group antigen can be specifically blocked by anti-A antibodies. To further evaluate the potential effect of the ABO polymorphism on the epidemiology of SARS, we present a model of its transmission dynamics that takes into account the effect of the protection by anti-histo-blood group natural antibodies.