EV71 infection induces neurodegeneration via activating TLR7 signaling and IL-6 production

Luo, Zhen; Su, Rui; Wang, Wenbiao; Liang, Yicong; Zeng, Xiaofeng; Shereen, Muhammad Adnan; Bashir, Nadia; Zhang, Qi; Zhao, Ling; Wu, Kailang; Liu, Yingle; Wu, Jianguo

doi:10.1371/journal.ppat.1008142

Cited by 71 publications

(52 citation statements)

References 55 publications

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“…EV71 infection predominantly induces type III IFN production in human IECs. EV71 is a highly infectious RNA virus causing epidemics of hand, foot, and mouth disease (HFMD) and neurological diseases through early infection of host intestine (4,32,33). In this study, we attempted to investigate the effect of EV71 on the induction of IFN signaling in intestine epithelial cells (IECs).…”

Section: Resultsmentioning

confidence: 99%

The TLR3/IRF1/Type III IFN Axis Facilitates Antiviral Responses against Enterovirus Infections in the Intestine

Shereen

Zeng

et al. 2020

mBio

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Enteroviruses infect gastrointestinal epithelium cells, cause multiple human diseases, and present public health risks worldwide. However, the mechanisms underlying host immune responses in intestinal mucosa against the early enterovirus infections remain elusive. Here, we showed that human enteroviruses including enterovirus 71 (EV71), coxsackievirus B3 (CVB3), and poliovirus 1 (PV1) predominantly induce type III interferons (IFN-λ1 and IFN-λ2/3), rather than type I interferons (IFN-α and IFN-β), in cultured human normal and cancerous intestine epithelial cells (IECs), mouse intestine tissues, and human clinical intestine specimens. Mechanistic studies demonstrated that IFN-λ production is induced upon enterovirus infection through the Toll-like receptor 3/interferon regulatory factor 1 (TLR3/IRF1) signaling pathway in IECs. In turn, the supplementation of IFN-λ subsequently induces intrinsically antiviral responses against enterovirus replication. Notably, intraperitoneal injection in neonatal C57BL/6J mice with mouse recombinant IFN-λ2 protein represses EV71 replication and protects mice from viral lethal effects. Altogether, these results revealed a distinct mechanism by which the host elicited immune responses against enterovirus infections in intestine through activating the TLR3/IRF1/type III IFN axis. The new findings would provide an antiviral strategy for the prevention and treatment of enterovirus infections and associated diseases. IMPORTANCE Enterovirus infections are significant sources of human diseases and public health risks worldwide, but little is known about the mechanism of innate immune response in host intestine epithelial surface during the viral replication. We reported the epithelial immune response in cultured human normal and cancerous cells (IECs), mouse tissues, and human clinical intestine specimens following infection with enterovirus 71. The results mechanistically revealed type III interferons (IFN-λ1 and IFN-λ2/3), rather than type I interferons (IFN-α and IFN-β), as the dominant production through TLR3/IRF1 signaling upon multiple human enterovirus infection, including enterovirus 71 (EV71), coxsackievirus B3 (CVB3), and poliovirus 1 (PV1). IFN-λ subsequently induced antiviral activity against enterovirus replication in vitro and in vivo. These studies uncovered the role of the novel process of type III IFN production involved in the TLR3/IRF1 pathway in host intestine upon enterovirus infection, which highlighted a regulatory manner of antiviral defense in intestine during enterovirus infection.

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Section: Resultsmentioning

confidence: 99%

The TLR3/IRF1/Type III IFN Axis Facilitates Antiviral Responses against Enterovirus Infections in the Intestine

Shereen

Zeng

et al. 2020

mBio

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“…Enterovirus 71 (EV71) is a common pathogen of hand, foot, and mouth disease (HFMD) in children, and it is also the most important risk factor for severe cases and deaths [ 1 – 4 ].Some children with HFMD can have severe neurological effects, such as aseptic meningitis, encephalitis and acute delayed paralysis, develop serious brainstem encephalitis, neurogenic pulmonary oedema and even die [ 5 , 6 ]. Children with severe neurological diseases who survive often have irreversible sequelae, seriously threatening their health [ 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

Molecular characteristics of the VP1 region of enterovirus 71 strains in China

2020

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Background: Enterovirus 71 (EV71) is the most commonly implicated causative agent of severe outbreaks of paediatric hand, foot, and mouth disease (HFMD).VP1 protein, a capsid protein of EV71, is responsible for the genotype of the virus and is essential for vaccine development and effectiveness. However, the genotypes of EV71 isolates in China are still not completely clear. Methods: The VP1 gene sequences of 3712 EV71 virus strains from China, excluding repetitive sequences and 30 known EV71 genotypes as reference strains, between 1986 and 2019 were obtained from GenBank. Phylogenetic tree, amino acid homology, genetic variation and genotype analyses of the EV71VP1 protein were performed with MEGA 6.0 software. Results: The amino acid identity was found to be 88.33%-100% among the 3712 EV71 strains, 93.47%-100% compared with vaccine strain H07, and 93.04%-100% compared with vaccine strains FY7VP5 or FY-23 K-B. Since 2000, the prevalent strains of EV71 were mainly of the C4 genotype. Among these, the C4a subgenotype was predominant, followed by the C4b subgenotype; other subgenotypes appeared sporadically between 2005 and 2018 in mainland China. The B4 genotype was the main genotype in Taiwan, and the epidemic strains were constantly changing. Some amino acid variations in VP1 of EV71 occurred with high frequencies, including A289T (20.99%), H22Q (16.49%), A293S (15.95%), S283T (15.11%), V249I (7.76%), N31D (7.25%), and E98K (6.65%). Conclusion: The C4 genotype of EV71 in China matches the vaccine and should effectively control EV71. However, the efficacy of the vaccine is partially affected by the continuous change in epidemic strains in Taiwan. These results suggest that the genetic characteristics of the EV71-VP1 region should be continuously monitored, which is critical for epidemic control and vaccine design to prevent EV71 infection in children.

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“…In previous studies, it was demonstrated that HFMD patients with EV-A71 and CV-A16 infections presented with significantly different clinical manifestations. EV-A71 infections frequently lead to severe central nervous system (CNS) complications and even death, while CV-A16 infections often result in milder symptoms that resolve within a few weeks [15]. Nevertheless, over the past years, accumulating evidence has revealed that HFMD in patients infected with CV-A16 can also develop into a serious stage with neurological complications, and the overall condition of these patients and their clinical symptoms are generally consistent with those of severe HFMD patients infected with EV-A71 [16].…”

Section: Introductionmentioning

confidence: 99%

Transcriptome analysis following enterovirus 71 and coxsackievirus A16 infection in respiratory epithelial cells

Liu

et al. 2020

Arch Virol

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Enterovirus 71 (EV-A71) and coxsackievirus A16 (CV-A16) are the major pathogens responsible for hand, foot and mouth disease (HFMD), but the mechanism by which these viruses cause disease remains unclear. In this study, we used transcriptome sequencing technology to investigate changes in the transcriptome profiles after infection with EV-A71 and CV-A16 in human bronchial epithelial (16HBE) cells. Using systematic bioinformatics analysis, we then searched for useful clues regarding the pathogenesis of HFMD. As a result, a total of 111 common differentially expressed genes were present in both EV-A71-and CV-A16-infected cells. A trend analysis of these 111 genes showed that 91 of them displayed the same trend in EV-A71 and CV-A16 infection, including 49 upregulated genes and 42 downregulated genes. These 91 genes were further used to conduct GO, pathway, and coexpression network analysis. It was discovered that enriched GO terms (such as histone acetylation and positive regulation of phosphorylation) and pathways (such as glycosylphosphatidylinositol (GPI)anchor biosynthesis and DNA replication) might be closely associated with the pathogenic mechanism of these two viruses, and key genes (such as TBCK and GPC) might be involved in the progression of HFMD. Finally, we randomly selected 10 differentially expressed genes for qRT-PCR to validate the transcriptome sequencing data. The experimental qRT-PCR results were roughly in agreement with the results of transcriptome sequencing. Collectively, our results provide clues to the mechanism of pathogenesis of HFMD induced by EV-A71 and CV-A16.

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EV71 infection induces neurodegeneration via activating TLR7 signaling and IL-6 production

Cited by 71 publications

References 55 publications

The TLR3/IRF1/Type III IFN Axis Facilitates Antiviral Responses against Enterovirus Infections in the Intestine

The TLR3/IRF1/Type III IFN Axis Facilitates Antiviral Responses against Enterovirus Infections in the Intestine

Molecular characteristics of the VP1 region of enterovirus 71 strains in China

Transcriptome analysis following enterovirus 71 and coxsackievirus A16 infection in respiratory epithelial cells

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