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. Author manuscript; available in PMC: 2025 Jun 1.
Published in final edited form as: Nat Rev Microbiol. 2025 Jan 17;23(6):385–401. doi: 10.1038/s41579-024-01144-9

Fig. 4 |. Distinct entry pathways and replication of bile acid-dependent GII.3 and bile acid-independent GII.4 into human intestinal enteroids.

Fig. 4 |

a, Each virus uses a different entry pathway. GII.3 requires sphingosine-1-phosphate receptor 2 (S1PR2) and bile acid to induce endocytosis (left panel), whereas GII.4 causes initial membrane injury and wound repair mechanisms to induce clathrin-independent carrier (CLIC)-mediated endocytosis (right panel). Common elements include initial binding to histoblood group antigens (HBGAs), putative receptor clustering in lipid rafts, endosomal acidification and lysosomal exocytosis that results in ceramide (Cer) appearance on the cell surface. b, The table highlights strain-specific differences in the biology of GII.3 and GII.4 viruses related to the requirement for FUT2 gene expression69,88, cell entry72,94, bile acid dependence69,72, acid sphingomyelinase involvement72,94, effects of JAK1/JAK2 inhibition100, effects of knockout of innate immune factors99 and host transcriptional responses99,100,231,232. ASM, acid sphingomyelinase; Gal-3, Galectin-3; IFN, interferon; SM, sphingomyelinase; V-ATPase, vacuolar-type ATPase.