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. 2024 Mar 7;6(3):171–177. doi: 10.1016/j.bsheal.2024.03.003

Caspase-8 activation regulates enterovirus D68 infection-induced inflammatory response and cell death

Yuanyuan Zhou a, Chongtao Zhang b, Yuhan Zhang a, Fei Li a, Jun Shen a,⁎
PMCID: PMC11894973  PMID: 40078725

Highlights

  • •

    Scientific question: The inflammatory response and cell death induced by enterovirus D68 (EV-D68) are currently not clearly classified. The main scientific issue of this study is to explore the association between caspase-8 and the inflammatory response and cell death caused by EV-D68.

  • •

    Evidence before this study: It has been reported that EV-D68 infection can activate caspase-3 for virus replication, and caspase-8 and caspase-9, the upstream proteins of caspase-3, are also activated prior to caspase-3 activation. Moreover, our previous research revealed that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) triggered inflammatory responses and cell death by caspase-8 activation.

  • •

    New findings: Inflammatory cytokines including tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), CCL-5 and CXCL-5 mRNA transcription were upregulated in a multiplicity of infection (MOI)-dependent manner after EV-D68 infection. EV-D68 infection activates caspase-8 to trigger necroptosis and apoptosis pathways.

  • •

    Significance of the study: This study demonstrates that EV-D68 infection activates caspase-8 to regulate inflammatory response and cell death, which can provide a new future therapeutic strategy for EV-D68 by inhibiting caspase-8 activation.

Keywords: Enterovirus D68 (EV-D68), Inflammatory response, Cell death, Caspase-8

Abstract

Enterovirus D68 (EV-D68) infection causes severe acute respiratory infection and severe neurological complications, such as acute flaccid myelitis (AFM), in children. However, although EV-D68 has pandemic potential, no effective drugs or vaccines are currently clinically available. Furthermore, EV-D68 infection-induced inflammatory response and cell death are not fully understood. In this study, we demonstrated that several inflammatory cytokines were upregulated in a multiplicity of infection (MOI) dependent manner in EV-D68-infected human rhabdomyosarcoma (RD) cells. Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) confirmed that tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), C-C motif chemokine ligand-5 (CCL-5), and CXC motif chemokine ligand-5 (CXCL-5) mRNA levels were highly upregulated after EV-D68 infection. IL-1β processing and maturation mediated by caspase-8 was inhibited by the caspase-8 inhibitor Z-IETD-FMK. EV-D68 infection activates caspase-8 to mediate IL-1β maturation and secretion. Additionally, EV-D68 activated cell death-related proteins such as caspase-3, poly (ADP-ribose) polymerase 1 (PARP-1), phosphorylation of Mixed Lineage Kinase domain-like protein (pMLKL), and gasdermin E (GSDME). Thus, EV-D68 infection activates caspase-8, which triggers the necroptosis and apoptosis pathways. Overall, our data suggest that caspase-8 activation is associated with the inflammatory response and cell death in EV-D68-infected RD cells. This mechanism represents a novel target for the treatment of EV-D68 infection by inhibiting caspase-8 activation.

1. Introduction

In 2014, more than 2,000 cases of enterovirus D68 (EV-D68) infection were reported in 20 countries worldwide [1]. EV-D68 infection is associated with neurological diseases such as acute flaccid myelitis (AFM), which presents as paralysis symptoms similar to polio [2], [3], [4], [5]. The widespread distribution and rapid mutation of EV-D68 pose a pandemic threat, especially in children [6], [7]. Currently, no antiviral medicine or vaccine is clinically available for EV-D68 [8], [9]. Therefore, understanding the pathogenesis of EV-D68 is critical to identifying potential antiviral targets.

Recent studies have shown that a viral-induced cytokine storm can cause more damage to cells and tissues than the direct effects of viral attack, as reported for influenza virus, enterovirus A71 (EV-A71), coxsackievirus (CV-A6), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [10], [11], [12], [13]. EV-D68 infection induces profound transcriptional dysregulation of host genes in human rhabdomyosarcoma (RD) cells, leading to significantly elevated inflammatory responses and altered antiviral immune responses [14], [15].

Cell death programs play a pivotal role in maintaining tissue and organ function; apoptosis, necroptosis, and pyroptosis are the three major cell death programs. Caspases are involved in cell death, immune responses, and virus production, as shown by studies. Currently, caspase-8 is considered to be a master regulator of apoptosis, necroptosis, and pyroptosis, as it can regulate the expression of inflammatory genes and promote the production of proinflammatory cytokines, thus driving inflammatory responses [16], [17], [18], [19]. Our previous research showed that SARS-CoV-2 could trigger inflammatory responses and induce a dual mode of cell death in Calu-3 cells through caspase-8 activation [20]. Additionally, caspase-3 reportedly is activated and induces host cell apoptosis during EV-D68 replication [21].

In this study, our objective was to explore the role of caspases, especially caspase-8, in the inflammatory response and cell death pathways induced by EV-D68 infection. These findings could help identify new strategies to treat EV-D68 infection.

2. Materials and methods

2.1. Viruses and cells

The prototype strain Fermon (GenBank accession no. AY426531) and pBluescriptII SK-vector based EV-D68 15296 strain were obtained from the National Institute for Food and Drug Control (China) [22]. The RD cell line was purchased from American Type Culture Collection (ATCC, USA). Cells were cultured in a humidified atmosphere with supply of 5 % CO2 at 37 °C. All viruses were grown in RD cells which were then treated with three freeze–thaw cycles, the cellular debris were clarified by centrifugation at 3,900 × g for 10 min at 4 °C. Afterwards the supernatant was filtered through a syringe filter (0.2 μm; Pall Corporation, Germany), and the purified virions were aliquoted and stored at −80 °C until use.

2.2. Antibodies and reagents

The antibodies and reagents were prepared as previously reported [18]. Antibodies including rabbit anti-NLRP3, anti-caspase-9, anti-caspase-8, anti-caspase-3, anti-cleaved-caspase-3, anti-BID, anti-caspase-1, anti-mixed lineage kinase domain (MLKL), anti-pMLKL, and anti-poly (ADP-ribose) polymerase1 (PARP-1) were purchased from Cell Signaling Technology (Beverly, MA, USA). Polyclonal anti-interleukin-1β (anti-IL-1β) antibody was purchased from Abclonal (Wuhan, China) and the polyclonal rabbit anti-α-tubulin was purchased from Proteintech (Chicago, IL, USA).

2.3. Ribonucleic acid (RNA) isolation and qRT–PCR analysis

Cellular RNA was extracted with the RNAiso Plus Kit according to the description of the manufacturer (TAKARA, Japan). qRT–PCR analysis was performed using a two-step procedure with the HiScript III 1st Strand cDNA Synthesis Kit (Vazyme, China) and ChamQ Universal SYBR qPCR Master Mix (Vazyme, China) according to the description of the manufacturer respectively.

2.4. Western blotting analysis

Cells were washed, harvested, and lysed with the cell lysis buffer according to the description of the manufacturer (Beyotime, China). Cell lysates were analyzed with 10 % to 15 % sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis and then transferred to polyvinylidene difluoride membranes (Millipore, Bedford, USA). After blocking with bovine serum albumin (BSA), proteins were probed with the indicated primary antibodies followed by detection with the corresponding horseradish peroxidase-conjugated secondary antibodies. Protein bands were detected using an enhanced chemiluminescence kit (Millipore, Bedford, USA) according to the description of the manufacturer.

2.5. Data analysis

The statistical analyses were performed with GraphPad Prism version 6 (GraphPad Software, San Diego, CA). A probability (P) value of <0.05 was considered statistically significant.

3. Results

3.1. EV-D68 infection induces an inflammatory response in RD cells

Both the prototype Fermon strain and the pBluescriptII strain SK-vector-EV-D68 15,296 were used to establish in vitro models of infected RD cells (Fig. 1). Quantitative reverse transcriptase PCR (qRT–PCR) analysis detected multiplicity of infection (MOI)-dependent upregulation of several inflammatory cytokines and chemokines, including tumor necrosis factor-α (TNF-α), IL-6, C-C motif chemokine ligand-5 (CCL-5), and CXC motif chemokine ligand-10 (CXCL-10), in virus-infected RD cells (Fig. 2A–D). Viral infection of RD cells also induced IL-1β (P17) in an MOI-dependent manner (Fig. 2A–D). Furthermore, pro-IL-1 expression of pro-IL-1β was upregulated in infected cells. Additionally, Western blotting revealed that expression of viral protein 1 (VP1) increased in an MOI-dependent manner at 48 h post-infection (h.p.i.) (Fig. 2E and F).

Fig. 1.

Fig. 1

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The establishment of EV-D68 infected cell models. In vitro CPE of RD infected with Fermon and pBluescriptII SK-vector-EV-D68 15,296 strains at MOI of 0.1, 1, or 10 at 24 h and 48 h, respectively. Scale bars: 100 μm. Abbreviations: EV-D68, enterovirus D68; RD, rhabdomyosarcoma; CPE, cytopathic effect assay; MOI, multiplicity of infection.

Fig. 2.

Fig. 2

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EV-D68 infection induces inflammatory responses. RD cells were infected with EV-D68 at MOIs of 1, 5, or 10 for 48 h. Cellular TNF-α, IL-6, CCL-5, and CXCL-5 mRNA expression was quantified using qRT–PCR (A–D). Intracellular expression of pro-IL-1β and mature IL-1β (P17) was measured by western blotting (E and F). Abbreviations: EV-D68, enterovirus D68; RD, rhabdomyosarcoma; MOI, multiplicity of infection; VP1, viral protein 1; h.p.i., hours post-infection; TNF-α, tumor necrosis factor-α; IL, interleukin; CCL-5, C-C motif chemokine ligand-5; CXCL-5, CXC motif chemokine ligand-5.

3.2. EV-D68 infection activates caspase-8, which mediates IL-1β maturation

Previous research has demonstrated that caspase-8 can process pro-IL-1β into mature IL-1β, in the same manner as caspase-1 [20]. Therefore, we analyzed caspase-8 activation and IL-1β processing and secretion. RD cells were mock treated or infected with viruse at MOIs of 1, 5, or 10 for 48 h; cells treated with staurosporine (STS, 1 μmol/L), which was a nonselective protein kinase inhibitor, were used as a positive control. RD cells infected with the virus for 48 h were subjected to Western blotting using the indicated antibodies. Viral infection of RD cells induced a pronounced cleavage of caspase-8. Detection of cleavage of the BH3-interacting of the domain (BID) death agonist, a substrate of caspase-8 and caspase-1, in the truncated form further confirmed the activation of caspase-8 in the virus-infected cells (Fig. 3A).

Fig. 3.

Fig. 3

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EV-D68 infection activates caspase-8 to promote IL-1β maturation. A) EV-D68-infected RD cells were subjected to western blotting using the indicated antibodies at 48 h.p.i. Cells treated with the STS pan protein kinase inhibitor STS were used as a positive control. B) Western blots at 48 h.p.i. of RD cells infected with EV-D68 and treated with the caspase-8-specific inhibitor IETD. C) The LDH release test showed that IETD had no significant effect on cell membrane integrity and cytotoxicity. D) Western blots at 48; h.p.i. of RD cells infected with EV-D68 and treated with the pan-caspase inhibitors IETD, VAD, and DEVD. Abbreviations: EV-D68, enterovirus D68; IL, interleukin; RD, rhabdomyosarcoma; PARP1, poly (ADP-ribose) polymerase1; VP1, viral protein 1; BID, BH3-interacting domain; h.p.i., hours post-infection; LDH, lactate dehydrogenase; STS, staurosporine; IETD, Z-IETD-FMK; VAD, Z-VAD-FMK; DEVD, Z-DEVD-FMK.

Next, we processed cells infected with EV-D68 using different caspase inhibitors. The mature IL-1β (P17) levels in the supernatant and intracellular levels of pro-IL-1β were determined by western blotting. Z-IETD-FMK, a caspase-8-specific inhibitor, strongly reduced IL-1β processing and secretion in virus-infected cells in a concentration-dependent manner. Simultaneously, they had no significant impact on cell membrane integrity and cytotoxicity (Fig. 3B and C). Z-VAD-FMK and Z-DEVD-FMK, which had broader inhibitory effects on caspase-3, caspase-7, caspase-8, and caspase-10, led to similar reductions in P17 levels in virus-infected cells (Fig. 3D). Viral VP1 expression remained relatively stable in cells treated with the inhibitors at 48 h.p.i., indicating that the caspase inhibitors did not affect viral replication. Thus, these results suggested that EV-D68 infection activated caspase-8 and mediates the maturation of IL-1β.

3.3. EV-D68 infection activates caspase-8 to mediate IL-1β secretion and triggers both necroptosis and apoptosis pathways

Next, we analyzed IL-1β secretion in EV-D68-infected RD cells. When infected at a MOI of 10, EV-D68-infected RD cells exhibited a significant inflammatory response at 48 h, inducing elevated intracellular and extracellular IL-1β levels (Fig. 4). Furthermore, EV-D68 infection of RD cells also induced phosphorylation of MLKL, the effector of necroptosis that is phosphorylated by receptor-interacting protein kinase (RIPK)-3 during necroptosis. Additionally, cleavage of PARP-1, a hallmark of activation of apoptosis, was observed in infected cells (Fig. 3, Fig. 4, Fig. 5).

Fig. 4.

Fig. 4

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EV-D68 infection activates caspase-8 to promote IL-1β secretion. The levels of pro-IL-1β, P17, and VP1 proteins in the supernatants and cell levels were determined by western blotting at 24 and 48 h.p.i. Abbreviations: EV-D68, enterovirus D68; IL, interleukin; BID, BH3-interacting domain; RARP, Rickettsia ankyrin repeat protein; VP1, viral protein 1; h.p.i., hours post-infection; RD, rhabdomyosarcoma.

Fig. 5.

Fig. 5

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EV-D68 infection activates caspase-8 triggering necroptosis and apoptosis pathways. RD cells were mock-treated or infected with EV-D68 with the indicated indicator MOI (MOI = 1, 5, or 10) for 48 h. VP1 levels in the supernatants and intracellular levels of MLKL, pMLKL, GSDME, and C-GSDME were determined by western blotting. Abbreviations: EV-D68, enterovirus D68; RD, rhabdomyosarcoma; MOI, multiplicity of infection; VP1, viral protein 1; MLKL, mixed lineage kinase domain; GSDME, Gasdermin E; C-GSDME, Cleavage of gasdermin E; PARP1, poly (ADP-ribose) polymerase 1; h.p.i, hours post-infection.

4. Discussion and conclusions

This study demonstrates that caspase-8 triggers an inflammatory response and cell death in RD cells infected with EV-D68. During the last decade, our understanding of the function of caspase-8 has changed. Previously thought to be exclusively an apoptotic caspase, it has now emerged as a master regulator of the three major cell death pathways, including apoptosis, pyroptosis, and necroptosis [18]. Pathogen infection activates caspase-8, which plays an important role in inflammasome activation, cell death, and cytokine induction. We found that both Fermon and pBluescriptII SK-vector-EV-D68 15296 could induce the activation of caspase-8 activation to trigger the necroptosis and apoptosis pathways. Furthermore, activated caspase-8 directly stimulates the processing of pro-IL-1β into mature IL-1β (Fig. 6). Caspase-8 is known to be an important effector of NLRP3 inflammasome signaling, which drives the processing and maturation of IL-1β [17].

Fig. 6.

Fig. 6

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A proposed model of EV-D68 infection’s inflammatory response and cell death induction. EV-D68 infection induces cell death through activation of caspase-8, which in turn promotes IL-1β processing and maturation. Abbreviations: EV-D68, enterovirus D68; RD, rhabdomyosarcoma; RIPK3, receptor-interacting protein kinase-3; MLKL, mixed lineage kinase domain.

The innate immune system is critical for host resistance to EV-D68 infection. Upon recognition of pathogen-associated molecular patterns in viruses, host cell pattern recognition receptors (RPRs) trigger intracellular signaling cascades to activate proinflammatory responses. Cytokine storm, the excessive secretion of cytokines leading to tissue damage, has been linked to the severity of viral diseases. Anti-inflammatory and immunomodulatory treatments have been proposed as potential therapeutic approaches for EV-D68 infection [14], [23], [24]. The dysfunction and/or death of motor neurons involved in AFM may occur due to lytic cell death and activate proinflammatory responses. Targeting caspase 8 may prevent or reduce the severity of AFM.

Recently, EV-D68 infection was reported to activate caspase-3 during viral replication. Furthermore, caspase-8, and caspase-9, the upstream proteins of caspase-3, were activated before caspase-3 was activated in infected cells [21], [25], [26]. Similar to what we observed in SARS-CoV-2 infection, we found that EV-D68 infection activated caspase-8, triggering the necroptosis and apoptosis pathways [20]. A role for caspase-8 in the regulation of inflammatory responses and cell death has recently been reported in the context of pathogen infection. Caspase-8-mediated apoptosis or pyroptosis and inflammatory responses in infected lung epithelial cells may induce downstream immune pathogenesis in lung tissues [27]. Necroptosis, another form of programmed cell death that is distinct from apoptosis, relies on MLKL activation by RIPK1 and RIPK3 [11], [12], [16]. Activated caspase-8 inhibits the necroptosis pathway mediated by RIPK3 and MLKL. However, in this study, activated caspase-8 promoted the processing and maturation of IL-1β and triggered both necroptosis and apoptosis pathways in EV-D68-infected RD cells. Combined with the literature, our findings indicate that regulated caspase-8 activation may, in turn, activate the necroptosis pathway. Further research is required to identify how EV-D68 triggers regulate caspase-8 activation and the necroptosis pathway to induce an inflammatory response.

Pyroptosis is emerging as another important type of programmed cell death. Pyroptosis is mediated by the gasdermin (GSDM) family, which mainly includes GSDMA, GSDMB, GSDMC, GSDMD, and GSDME, which induce the release of inflammatory factors such as IL-1β and IL-18, leading to an inflammatory response [27], [28]. In recent years, pyroptosis pathways have been found to include the canonical inflammasome-induced pathway, the noncanonical inflammasome-induced pathway, the caspase-1/3/6/7/GSDMB pathway, the caspase-8/GSDMC pathway, the caspase-8/GSDMD pathway, and the caspase-3/GSDME pathway [28]. In our study, we observed the activation of GSDME in EV-D68-infected RD cells. GSDME is cleaved by caspase-3, which is dependent on the activation of the upstream factors caspase-8 and caspase-9. However, further research is needed to determine how EV-D68 induces pyroptosis via the crucial GSDM protein and to delineate the role of caspase-8 in pyroptosis.

In conclusion, several proinflammatory cytokines and chemokines were upregulated in EV-D68-infected RD cells. EV-D68 infection triggered a dual mode of cell death in the RD cell line through the activation. Our data suggest that blocking caspase-8 activation blockade may represent an effective therapeutic strategy for treating patients with severe EV-D68 infections [29].

Acknowledgements

The authors thank Professor Zhenglun Liang of the China National Institute of Food and Drug Control for providing the Fermon strain (GenBank accession number AY426531) and pBluescriptII SK-vector-EV-D68 15296. This work was partially supported by the Shanghai Science and Technology Commission Medical Project (grant 21Y11901300), the Contagious and Infectious Diseases Specialist Alliance (SHDC22021317), and the National Key Research and Development Program of China (2022YFC2704900).

Conflict of interest statement

The authors declare that there are no conflicts of interest.

Author contributions

Yuanyuan Zhou: Methodology, Investigation, Writing – original draft. Chongtao Zhang: Data curation, Writing – original draft, Validation. Yuhan Zhang: Data curation, Software. Fei Li: Data curation, Software. Jun Shen: Conceptualization, Funding acquisition, Supervision, Writing – review & editing.

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