Discovery of a proteinaceous cellular receptor for a norovirus

Abstract

Human noroviruses (NoV) are a leading cause of gastroenteritis globally, yet host factors required for NoV infection are poorly understood. We identified host molecules essential for murine NoV (MNoV) induced cell death including CD300lf as a proteinaceous receptor. CD300lf is essential for MNoV binding and replication in cell lines and primary cells. Additionally, Cd300lf−/− mice are resistant to MNoV infection. Expression of CD300lf in human cells breaks the species barrier restricting MNoV replication. The crystal structure of the CD300lf ectodomain revealed a potential ligand binding cleft composed of residues critical for MNoV infection. Therefore, the presence of a proteinaceous receptor is the primary determinant of MNoV species tropism while other components of cellular machinery required for NoV replication are conserved between humans and mice.

The Role of Interferon in Persistent Viral Infection: Insights from Murine Norovirus

“…The protruding domain of the capsid gene binds cell surface carbohydrates and the proteinaceous MNV receptor, CD300lf [55,73]. This domain is also the determinant of early IFN responses in MLNs [72], spread to extra-intestinal tissues (systemic spread) [54], and lethality in Stat1 −/− mice [52,74].…”

“…IECs do not commonly express the MNV receptor, CD300lf, whereas myeloid cells express it abundantly [73,94,95]. Additionally, work from our lab and others have not found MNV to grow in IECs in vitro unless they ectopically express CD300lf [68].…”

The Dual Tropism of Noroviruses

“…MNV-1 and the persistent strain MNV-S99 (20) bind to terminal sialic acids on gangliosides and Nand O-linked glycoproteins, while MNV-CR3 binds to N-linked glycoproteins (18,19). Following attachment to the cell surface, at least three strains, MNV-1 (specifically its plaque-purified isolate CW3), MNV-CR6, and MNV-S7, use the CD300 family member CD300lf as the viral receptor (Table 1) (21)(22)(23). This family of proteins has a single immunoglobulin variable-like (IgV) extracellular domain that is involved in the regulation of immune responses (24,25).…”

“…CD300lf is expressed on immune cells and binds phosphatidylserine (PS) to regulate phagocytosis of apoptotic cells and elicit a range of other immune-inhibitory functions. Deletion of CD300lf from cells renders them nonsusceptible to MNV-1 and MNV-CR6, while expression of the molecule converts nonsusceptible cells into susceptible cells (21,22). CD300ld is a paralog of CD300lf that shares the N-terminal portion of the protein with CD300lf, and it can also confer MNV susceptibility to nonsusceptible cells (22).…”

“…Deletion of CD300lf from mice renders them resistant to MNV-1 and MNV-CR6 infection (21,31). Studies using bone marrow transplants between wild-type (wt) and CD300lf-deficient mice aimed at identifying the infected cell type revealed that during the persistent phase of the infection (i.e., 21 days postinfection), MNV-CR6 required wt radiation-resistant cells (e.g., epithelial cells) (31).…”