CD300lf is the primary physiologic receptor of murine norovirus but not human norovirus

Abstract

Murine norovirus (MNoV) is an important model of human norovirus (HNoV) and mucosal virus infection more broadly. Viral receptor utilization is a major determinant of cell tropism, host range, and pathogenesis. The bona fide receptor for HNoV is unknown. Recently, we identified CD300lf as a proteinaceous receptor for MNoV. Interestingly, its paralogue CD300ld was also sufficient for MNoV infection in vitro. Here we explored whether CD300lf is the sole physiologic receptor in vivo and whether HNoV can use a CD300 ortholog as an entry receptor. We report that both CD300ld and CD300lf are sufficient for infection by diverse MNoV strains in vitro. We further demonstrate that CD300lf is essential for both oral and parenteral MNoV infection and to elicit anti-MNoV humoral responses in vivo. In mice deficient in STAT1 signaling, CD300lf is required for MNoV-induced lethality. Finally, we demonstrate that human CD300lf (huCD300lf) is not essential for HNoV infection, nor does huCD300lf inhibit binding of HNoV virus-like particles to glycans. Thus, we report huCD300lf is not a receptor for HNoV.

Vero Cells as a Mammalian Cell Substrate for Human Norovirus

“…We attempted to inhibit HuNoV entry into Vero cells using antibody blockade of CD300ld/CD300lf, and by saturating potential CD300ld/CD300lf binding sites using a CD300ld/CD300lf ectodomain peptide, but both treatments were unsuccessful [51]. These findings are consistent with the report that CD300ld/CD300lf are not receptors for HuNoV [64].…”

Experimental Methods to Study the Pathogenesis of Human Enteric RNA Viruses

“…Numerous MNoV studies have contributed substantially to our understanding of the cellular and molecular mechanisms of NoV pathogenesis, revealing important regulatory aspects of the commensal microbiota, IFN signaling, and roles for nonstructural proteins in antagonism of host responses which are conserved with HuNoV [ 124 , 207 , 208 , 209 ]. A recent set of studies identified CD300LF as the host protein which serves as the MNoV receptor, and though human CD300LF does not mediate the same role for HuNoV, this finding raises intriguing questions about the potential existence of a proteinaceous receptor for HuNoV [ 124 , 210 , 211 , 212 ]. More recently, murine astrovirus (muAstV) was identified as a small animal model for HAstVs [ 213 , 214 ].…”

Norovirus evolution in immunodeficient mice reveals potentiated pathogenicity via a single nucleotide change in the viral capsid

“…Adapted from (43). All images created using UCSF Chimera (63). https://doi.org/10.1371/journal.ppat.1009402.g008…”

“…We recently reported another surprising context in which F514I emerges: after intraperitoneal inoculation of Cd300lf +/-Stat1 -/and Cd300lf -/-Stat1 -/mice with high-dose CR6 [63]. Compared to lethal infection of Cd300lf +/-Stat1 -/littermates, intraperitoneal CR6 infection of mice lacking MNoV receptor CD300LF is significantly abrogated and is non-lethal.…”

“…MNoV TaqMan assays were performed, using a standard curve for determination of absolute viral genome copies, as described previously [77]. Quantitative PCR for housekeeping genes Rps29 or Actin was used to normalize absolute values of MNoV as previously described [33,63]. All samples were analyzed with technical duplicates.…”