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

作　　者：Yuanyuan Zhou Chongtao Zhang Yuhan Zhang Fei Li Jun Shen 

机构地区：[1]Children’s Hospital of Fudan University,National Children's Medical Center,Shanghai 201100,China [2]Wuhan Institute of Virology,Chinese Academy of Sciences,Wuhan 430071,China

出　　处：《Biosafety and Health》2024年第3期171-177,共7页生物安全与健康（英文）

基　　金：the China National Institute of Food and Drug Control for providing the Fermon strain(GenBank accession number AY426531)and pBluescriptII SK-vector-EV-D6815296;the Shanghai Science and Technology Commission Medical Project(grant 21Y11901300);the Contagious and Infectious Diseases Specialist Alliance(SHDC22021317);the National Key Research and Development Program of China(2022YFC2704900).

摘　　要：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.

关 键 词：Enterovirus D68(EV-D68) Inflammatory response Cell death CASPASE-8 

分 类 号：R512.5[医药卫生—内科学]