TREM-1 activation is a key regulator in driving severe pathogenesis of enterovirus 71 infection

Hand, foot and mouth disease (HFMD), caused by enterovirus 71 (EV71), presents mild to severe disease, and sometimes fatal neurological and respiratory manifestations. However, reasons for the severe pathogenesis remain undefined. To investigate this, infection and viral kinetics of EV71 isolates from clinical disease (mild, moderate and severe) from Sarawak, Malaysia, were characterized in human rhabdomyosarcoma (RD), neuroblastoma (SH-SY5Y) and peripheral blood mononuclear cells (PBMCs). High resolution transcriptomics was used to decipher EV71-host interactions in PBMCs. Ingenuity analyses revealed similar pathways triggered by all EV71 isolates, although the extent of activation varied. Importantly, several pathways were found to be specific to the severe isolate, including triggering receptor expressed on myeloid cells 1 (TREM-1) signaling. Depletion of TREM-1 in EV71-infected PBMCs with peptide LP17 resulted in decreased levels of pro-inflammatory genes, and reduced viral loads for the moderate and severe isolates. Mechanistically, this is the first report describing the transcriptome profiles during EV71 infections in primary human cells, and the involvement of TREM-1 in the severe disease pathogenesis, thus providing new insights for future treatment targets.