Collectively, this is the first report describing the immune mechanisms involved during EV-A71 infections in primary human cells, and the identification of novel pathways, such as triggering receptor expressed on myeloid cells 1 (TREM-1) signalling, that are unique and specific to the severe EV-A71 isolate, and likely contributing to the severe manifestations of the disease. The gene discussed is TREM1; the disease is infection.