Here, our data showed that SphK2-S1P-S1P2 was upstream of EGFR in meningitic E. coli invasion, and more importantly that the EGFR activation at 30 min after infection was abolished by treatment with the S1P2 antagonist JTE-013, implying that the early EGFR activation might arise from the S1P-S1P2 pathway, which involves GPCR-related signaling. Here, EGFR is linked to infection.