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

Abstract

word count: 175 words 27 Text word count: 5421 words 28 Abstract (175 words) 29Hand, foot and mouth disease (HFMD), caused by enterovirus 71 (EV71), presents 30 mild to severe disease, and sometimes fatal neurological and respiratory 31 manifestations. However, reasons for the severe pathogenesis remain undefined. To 32 investigate this, infection and viral kinetics of EV71 isolates from clinical disease (mild, 33 moderate and severe) from Sarawak, Malaysia, were characterized in human 34 rhabdomyosarcoma (RD), neuroblastoma (SH-SY5Y) and peripheral blood 35 mononuclear cells (PBMCs). High resolution transcriptomics was used to decipher 36 EV71-host interactions in PBMCs. Ingenuity analyses revealed similar pathways 37 triggered by all EV71 isolates, although the extent of activation varied. Importantly, 38 several pathways were found to be specific to the severe isolate, including triggering 39 receptor expressed on myeloid cells 1 (TREM-1) signaling. Depletion of TREM-1 in 40 EV71-infected PBMCs with peptide LP17 resulted in decreased levels of pro-41 inflammatory genes, and reduced viral loads for the moderate and severe isolates. 42Mechanistically, this is the first report describing the transcriptome profiles during 43 EV71 infections in primary human cells, and the involvement of TREM-1 in the severe 44 disease pathogenesis, thus providing new insights for future treatment targets. 45 48 mouth, feet and bottoms (1-3). Outbreaks of HFMD are caused by human enterovirus 49 group A members (HE-A), mainly coxsackieviruses A16, A6 and A10, and enterovirus 50 71 (EV71) (1, 4, 5). While often benign and self-limiting (2), the disease can cause 51 cardiopulmonary and neurological complications such as myocarditis, brainstem 52 encephalitis, aseptic meningitis, and neurogenic pulmonary edema, which can be fatal 53 (6, 7). The severe manifestations of HFMD are often associated with cases of EV71 54 infections, rather than coxsackievirus A16 (8). 55

Transcriptomic Profiling Reveals a Role for TREM-1 Activation in Enterovirus D68 Infection-Induced Proinflammatory Responses

“…Amrun et al reported that severe EV-A71 infection leads to activation of the TREM-1 signaling pathway, and LP17-mediated TREM-1 inhibition does not affect the replication of EV-A71 (27). Herein, we investigated whether the LP17-mediated downregulation of the TREM-1 signal pathway affects the replication of EV-D68.…”