Abstract
Hand, foot and mouth disease (HFMD), caused by enterovirus A71 (EV-A71), 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 EV-A71 isolates from clinical disease (mild, moderate and severe) from Sarawak, Malaysia, were characterised in human rhabdomyosarcoma (RD), neuroblastoma (SH-SY5Y) and peripheral blood mononuclear cells (PBMCs). High resolution transcriptomics was used to decipher EV-A71-host interactions in PBMCs. Ingenuity analyses revealed similar pathways triggered by all EV-A71 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) signalling. Depletion of TREM-1 in EV-A71-infected PBMCs with peptide LP17 resulted in decreased levels of pro-inflammatory genes for the moderate and severe isolates. Mechanistically, this is the first report describing the transcriptome profiles during EV-A71 infections in primary human cells, and the potential involvement of TREM-1 in the severe disease pathogenesis, thus providing new insights for future treatment targets.
Highlights
Hand, foot and mouth disease (HFMD), caused by enterovirus A71 (EV-A71), presents mild to severe disease, and sometimes fatal neurological and respiratory manifestations
Infection kinetics and high-density transcriptomic profiling by RNA-sequencing (RNA-seq) of EV-A71-infected peripheral blood mononuclear cells (PBMCs) revealed several virus severity-dependent differences. 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
Six EV-A71 isolates were identified from patients during an outbreak of HFMD in Sarawak, Malaysia, in 200622
Summary
Foot and mouth disease (HFMD), caused by enterovirus A71 (EV-A71), presents mild to severe disease, and sometimes fatal neurological and respiratory manifestations. Depletion of TREM-1 in EV-A71-infected PBMCs with peptide LP17 resulted in decreased levels of pro-inflammatory genes for the moderate and severe isolates This is the first report describing the transcriptome profiles during EV-A71 infections in primary human cells, and the potential involvement of TREM-1 in the severe disease pathogenesis, providing new insights for future treatment targets. Infection kinetics and high-density transcriptomic profiling by RNA-sequencing (RNA-seq) of EV-A71-infected peripheral blood mononuclear cells (PBMCs) revealed several virus severity-dependent differences. 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
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