Norovirus Recognition Sites on Histo-Blood Group Antigens

Norovirus (NoV) is the major causative agent of acute viral gastroenteritis worldwide. Based on genetic analyses, human NoV strains have been classified into at least three genogroups: genogroup I (GI), GII, and GIV, which contain at least 15, 18, and 1 genotypes, respectively (Kageyama et al., 2004). Notably, these NoV genotypes are morphologically similar to one another but differ antigenically (Kapikian, 1996; Estes et al., 1997; Hansman et al., 2006). Since no cell culture system has been developed yet, molecular analyses to elucidate the mechanisms underlying infection or productive replication have been stalled until recently. The primary NoV replication site in humans is unknown, but intestinal biopsy from volunteer who became ill following oral administration of NoV exhibited histopathologic lesions, in which the villi of the proximal small intestine were blunted (Agus et al., 1973). More than 30 years ago, the initial NoV challenge studies conducted in volunteers found that a subset of individuals was repeatedly susceptible to NoV infection, whereas a second subset was repeatedly resistant to infection (Parrino et al., 1977). A genetic factor, possibly a receptor, was hypothesized to affect the susceptibility of an individual to NoV infection. Recently, a mechanism that explains the susceptibility or resistance to NoV infection has been identified; namely, NoV attaches to histo-blood group antigens (HBGAs) on potential host cells in the gut (Lindesmith et al., 2003). HBGAs are structurally related oligosaccharides that include ABH antigens and Lewis (Le) antigens (Figure 1). Polymorphisms in the ABH antigens are induced by variations in the core structure. Type 1 chain ABH antigens are widely expressed in endodermally derived tissues such as the lining epithelia and the glandular epithelia (Oriol et al., 1986). Meanwhile, type 2 chain ABH antigens are found priof approximately 58 kDa are generated and self-assembled into VLPs (Xi et al., 1990; Jiang et al., 1993). Though artificial, these VLPs are morphologically and antigenically similar to those of the respective native virions (Jiang et al., 1992; Green et al., 1993; Prasad et al., 1994, 1999). VP1 has two major domains: a shell (S) domain, which forms the core of the icosahedral shell (Bertolotti-Ciarlet et al., 2002), and a protruding (P) domain, which forms arches extending from the shell and is responsible for host interactions (Tan et al., 2004, 2011; Tan and Jiang, 2005a,b, 2007). The association and dissociation kinetics for NoV VLPs binding to HBGAs were measured with SPR experiments (Choi et al., 2008; Shirato et al., 2008), which allowed us to visualize marily in ectoor meso-dermally derived tissues, including skin and erythrocytes (Hakomori, 1981; Dabelsteen et al., 1982; Oriol et al., 1986). In the human gastroduodenal junction, type 1 structures are found exclusively at the level of the surface epithelia, whereas type 2 structures are preferentially found at the glandular level (Mollicone et al., 1985). Details of the NoV recognition of HBGAs were clarified with in vitro experiments, enzyme-linked immunosorbent assays (ELISAs), and surface plasmon resonance (SPR) experiments using virus-like particles (VLPs), as well as crystallization studies using P domains. When the NoV VP1 gene, which encodes a capsid protein, is expressed in insect cells, capsid proteins