TREM-1 activation is a potential key regulator in driving severe pathogenesis of enterovirus A71 infection

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. Hand, foot and mouth disease (HFMD) is a febrile illness that predominantly affects infants and young children, and is characterised by rash and blisters on the hands, mouth, feet and bottoms 1-3. Outbreaks of HFMD are caused by human enterovirus group A members (HE-A), mainly coxsackieviruses A16, A6 and A10, and enterovirus A71 (EV-A71) 1,4,5. While often benign and self-limiting 2 , the disease can cause cardiopulmonary and neurological complications such as myocarditis, brainstem encephalitis, aseptic meningitis, and neurogenic pulmonary oedema, which can be fatal 6,7. The severe manifestations of HFMD are often associated with cases of EV-A71 infections, rather than coxsackievirus A16 8. EV-A71 belongs to the Enterovirus A species, Enterovirus genus, from the Picornaviridae family 9,10. The virus has a positive-sense RNA genome of 7.4 kb and encodes for four structural (VP1-4) and seven non-structural (2A-C and 3A-D) proteins 9. First isolated in California, USA, in 1969 11 , the virus is transmitted via the oral-foecal route, saliva and respiratory secretions 12. Based on the sequence analysis of VP1 gene, the virus can be broadly categorised into six genogroups: A, B, C, D, E and F 7,10,13. Whereas genogroup A contains the Californian prototype virus BrCr, genogroups B and C consist of various strains, and are further categorised into sub-genogroups B0-B5 and C1-C5 10. B and C genogroups are globally distributed, whereas D, and E and F are limited to India and Africa respectively 7,10. After the almost total eradication of poliovirus, EV-A71 is now noted as one of the most prevalent neurotropic enteroviruses, and is especially endemic in the Asia-Pacific region 14-17. Currently, the

Viral determinants that drive Enterovirus-A71 fitness and virulence

“…Thus, it appears that the ability of EV-A71 to manipulate its host immune system represents an integral part of its virulence strategy, and influences the clinical outcome. However, while some recent evidence support that EV-A71 strains associated with severe clinical outcome manipulate differently their host immune signalling pathways [ 64 ], the viral determinants involved have yet to be reported.…”

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 down-regulation of the TREM-1 signal pathway affects the replication of EV-D68.…”

sTREM-1 Predicts Disease Severity and Mortality in COVID-19 Patients: Involvement of Peripheral Blood Leukocytes and MMP-8 Activity

“…However, fever was not the most common sign among patients with COVID-19 in our cohort, especially in cases of mild and moderate disease. While the role of sTREM-1 in patients presenting severe COVID-19 remains unclear, a functional genomic analysis of PBMCs from individuals undergoing infection with enterovirus A71 (EV-A71) determined that activation of TREM-1 was correlated with clinical severity [35]. Interestingly, genetic variants within the gene encoding TREM-1 are associated with different levels of inflammation and with the development of sepsis [36] and severe malaria in which sTREM-1 levels were high [8].…”