590 AN ORGANOID-IMMUNE CELL CO-CULTURE PREDICTIVE MODEL TO TARGET HER2/PD-L1 POSITIVE GASTRIC CANCERS

detergent effects or classical farnesoid X receptor or Takeda G-protein-coupled receptor 5 signaling.Instead, replication involves another G-protein coupled receptor, sphingosine-1phosphate receptor 2 (S1PR2), and BA treatment of HIEs increases particle uptake.Interestingly, inhibition of S1PR2 only reduces GII.3 but not GII.4 infection, providing further demonstration of strain specific differences in HuNoV infection.We also found that GCDCA induces multiple cellular responses that promote GII.3 replication in HIEs, including (i) enhancing endosomal uptake, (ii) endosomal acidification and subsequent activity of endosomal/lysosomal enzyme acid sphingomyelinase (ASM), and (iii) enhancing ceramide levels on the apical membrane.Inhibitors of endosomal acidification or ASM reduce GII.3 infection and exogenous addition of ceramide alone permits infection.Furthermore, inhibition of lysosomal exocytosis of ASM, which is required for ceramide production at the apical surface, decreases GII.3 infection.Conclusion.Together, our results support a model where GII.3 exploits rapid BA-mediated cellular endo-lysosomal dynamic changes and cellular ceramide to enter and replicate in jejunal HIEs.