Table 2.

Host Genes Involved in MNoV Regulation. Mouse genes implicated in viral infection, innate immune control, and adaptive immune control of murine norovirus are presented. MNV-1 and MNV-1.CW3 (here CW3) are acute strains of MNoV that infect systemic organs and are cleared by wild-type (WT) mice, while CR3, CR6, MNV/Hannover, and MNV-3 are persistent strains of MNoV that infect the intestine, are shed into the feces, and are not cleared in WT mice.

Viral infection
Gene	Role	MNoV strain(s)	In vitro effect	In vivo effect	Refs
Cd300lf and CD300ld	Viral receptors	CW3/CR6	Myeloid cell lines and primary macrophages lacking Cd300lf or CD300ld are not infected	Oral CR6 infection is prevented in Cd300lf−/− mice	[44,45]
Rag2 and Il2rg	Development of Peyer’s patches and M cells	CW3/CR3	MNoV is transcytosed by M-cell-like murine intestinal epithelial mlCcl2 cells	Oral MNoV infection is reduced in mice lacking M cells	[37,38]
Innate immunity
Gene	Role	MNoV strain(s)	In vitro effect	In vivo effect	Refs
Mda5	Viral recognition	MNV-1	Higher viral replication and defective cytokine response in Mda5−/− dendritic cells	Higher viral replication in Mda5−/− mice	[64]
Tlr3	Viral recognition	MNV-1	No effect observed	Higher viral replication in Tlr3−/− mice	[64]
Nlrp6	Viral recognition	MNV-1	N/A	Higher viral replication and levels of fecal shedding in Nlrp6−/− mice, and virus persists in Nlrp6−/− mice	[65]
Irf3	Induction of IFN	CW3	Irf3−/−Irf7−/− dendritic cells and macrophages show higher viral replication, and macrophages show impaired IFN production	Higher viral replication in Irf3−/− mice	[60]
		CR6	N/A	Irf3−/− mice are resistant to the effects of antibiotics in preventing infection	[68]
Irf7	Induction of IFN	CW3	Irf3−/−Irf7−/− dendritic cells and macrophages show higher viral replication, and macrophages show impaired IFN production	Higher viral replication in Irf7−/− mice	[60]
Ifnar1	Type I IFN response	MNV-1/CW3	Ifnar1−/− dendritic cells and macrophages show higher viral replication	Ifnar1−/− mice succumb to lethal infection, virus replicates to higher level, and virus persists in conditional knockout mice lacking Ifnar1 in dendritic cells or macrophages	[8,9,60–63]
		CR6	N/A	Enteric virus infects systemically in Ifnar1−/− mice	[68,69]
Ifngr1	Type II IFN response	CW3	N/A	Addition of Ifngr1 deficiency to type I IFN receptor deficiency causes increased viral replication and mortality	[61,66]
Ifnlr1	Type III IFN response	CR6	N/A	Higher viral replication and levels of fecal shedding in Ifnlr1−/− mice, and Ifnlr1−/− mice are resistant to the effects of antibiotics in preventing infection	[67,68]
Stat1	Type I, II, and III IFN response	MNV-1/CW3	Stat1−/− dendritic cells and macrophages show higher viral replication, and Stat1 is required for IFN-γ-mediated inhibition of MNoV replication in macrophages	Stat1−/− mice succumb to lethal infection	[8,9,66]
		CR6	N/A	Higher viral replication and levels of fecal shedding in Stat1−/− mice, and Stat1−/− mice are resistant to the effects of antibiotics in preventing infection	[67,68]
Irf1	Type II IFN Response	CW3	Irf1 is required for IFN-γ-mediated inhibition of MNoV replication in macrophages	Addition of Irf1 deficiency to type I IFN receptor deficiency causes increased viral replication and mortality	[66]
Atg5-Atg12, Atg7, and Atg16L1	Type II IFN response	CW3	Atg5–Atg12, Atg7, and Atg16L1 are required for IFN-γ-mediated inhibition of MNoV replication in macrophages	Addition of macrophage-specific Atg5-deficiency to type I IFN receptor deficiency causes increased viral replication and mortality	[61]
		CR6	N/A	Persistent viral infection induces intestinal pathology in Atg16L1-hypomorphic mice, dependent upon TNF-α and IFN-γ, though viral levels are similar to wild-type mice	[71]
Il10	Anti-inflammatory cytokine	MNV/Hannover1	N/A	Persistent viral infection induces intestinal pathology in Il10-deficient mice; though overall viral levels are similar to wild-type mice, MNoV localization is altered at early time points in knockout mice	[72]
Adaptive immunity
Gene	Role	MNoV strain(s)	In vitro effect	In vivo effect	Refs
Rag1	B- and T-lymphocyte development	CW3/MNV-3	N/A	MNoV persists in Rag1−/− mice, and adoptively transferred immune splenocytes can clear infection; adoptively transferred MNV-specific CD8+ T cells can decrease viral loads	[63,73–75]
Ighm/muMt	B-lymphocyte development	CW3/MNV-3	N/A	MNoV persists in muMt−/− mice; adoptively transferred immune splenocytes derived from B-cell-deficient mice or antibody production-deficient mice are unable to efficiently clear persistent infection in Rag1−/− mice; B cells are critical for protective immunity	[63,73,74,76]
MHC II	CD4+ T-cell development	CW3/MNV-3	N/A	MHC II −/− mice have higher viral titers in the ileum than wild-type mice, but clear infection normally; CD4+ T cells are critical for protective immunity	[63,74,76]
MHC I and β2M	CD8+ T-cell development	CW3	N/A	MNoV persists in MHC I × β2M−/− mice for longer periods than in wild-type mice, but is eventually cleared; acute control of virus is also regulated by CD8+ T cells	[74,76]