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

Jinyu Li,Yazhi Su,Hongyun Liu,Yulu Chen,Yue Teng,Yujun Cui,Ruicun Liu,Shan Yang,Sihua Liu,Yajun Song,Tao Wang

doi:10.3389/fimmu.2021.749618

Abstract

Increasing cases related to the pathogenicity of Enterovirus D68 (EV-D68) have made it a growing worldwide public health concern, especially due to increased severe respiratory illness and acute flaccid myelitis (AFM) in children. There are currently no vaccines or medicines to prevent or treat EV-D68 infections. Herein, we performed genome-wide transcriptional profiling of EV-D68-infected human rhabdomyosarcoma (RD) cells to investigate host-pathogen interplay. RNA sequencing and subsequent experiments revealed that EV-D68 infection induced a profound transcriptional dysregulation of host genes, causing significantly elevated inflammatory responses and altered antiviral immune responses. In particular, triggering receptor expressed on myeloid cells 1 (TREM-1) is involved in highly activated TREM-1 signaling processes, acting as an important mediator in EV-D68 infection, and it is related to upregulation of interleukin 8 (IL-8), IL-6, IL-12p70, IL-1β, and tumor necrosis factor alpha (TNF-α). Further results demonstrated that NF-κB p65 was essential for EV-D68-induced TREM-1 upregulation. Moreover, inhibition of the TREM1 signaling pathway by the specific inhibitor LP17 dampened activation of the p38 mitogen-activated protein kinase (MAPK) signaling cascade, suggesting that TREM-1 mainly transmits activation signals to phosphorylate p38 MAPK. Interestingly, treatment with LP17 to inhibit TREM-1 inhibited viral replication and infection. These findings imply the pathogenic mechanisms of EV-D68 and provide critical insight into therapeutic intervention in enterovirus diseases.

Highlights

Enterovirus D68 (EV-D68), an emerging pathogen in humans, is a member of the Picornaviridae family [1, 2], and causes a wide range of respiratory symptoms and a series of severe complications
The EV-D68-susceptible RD cell line was used as an infection model of EV-D68, in which EV-D68 is capable of normal replication and proliferation [19, 20]
We performed enzyme-linked immunosorbent assay (ELISA) experiments to characterize the change in levels of triggering receptor expressed on myeloid cells 1 (TREM-1) downstream cytokines, and the results proved that IL-6, interleukin 8 (IL-8), tumor necrosis factor alpha (TNF-a), and others were upregulated in response to viral infection (Figures 3D–H)

Summary

Introduction

Enterovirus D68 (EV-D68), an emerging pathogen in humans, is a member of the Picornaviridae family [1, 2], and causes a wide range of respiratory symptoms and a series of severe complications. Previous studies has concluded that EV-D68 has become the predominant enterovirus type in hospitalized children with respiratory symptoms in Europe [3, 4] and Japan [5, 6]. Host cell pattern recognition receptors (PRRs) can recognize viral components through the pathogen-associated molecular patterns of viruses or other pathogens, and subsequently trigger intracellular signaling cascades to activate proinflammatory responses, which can induce an antiviral state in infected host cells [7, 8]. For evading and antagonizing the host innate immune response, viruses have evolved complex mechanisms [6]. Previous studies have reported that enterovirus has several inhibition mechanisms to diminish production of type I interferon, resulting in reduced host antiviral responses [9,10,11]. Our results indicated that EV-D68 2Apro cleaves TRAF3, inhibits type I interferon responses, and subverts the innate immune responses [13]

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