The Preferential Infection of Astrocytes by Enterovirus 71 Plays a Key Role in the Viral Neurogenic Pathogenesis

Feng, Mei; Guo, Shiwen; Fan, Shengtao; Zeng, Xiaofeng; Zhang, Ying; Liao, Yun; Wang, Jianbin; Zhao, Tiantian; Wang, Lichun; Che, Yanchun; Wang, Jingjing; Ma, Na; Liu, Longding; Yue, Lei; Li, Qihan

doi:10.3389/fcimb.2016.00192

Cited by 32 publications

(43 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…First, virus replication in brain cells may be restricted. This is supported by histopathological studies showing very few neurons in brain are infected with EV-A71 [59, 60]. EQI viruses failed to acquire the VP1-K244E mutation, presumably due to lower infectivity of neurons and suboptimal replication following direct inoculation into brain, resulting in low virulence in mice.…”

Section: Discussionmentioning

confidence: 90%

Electrostatic interactions at the five-fold axis alter heparin-binding phenotype and drive EV-A71 virulence in mice

Tee

Tan

Yogarajah

et al. 2019

Preprint

View full text Add to dashboard Cite

19Enterovirus A71 (EV-A71) causes hand, foot and mouth disease epidemics with neurological 20 complications and fatalities. However, the neuropathogenesis of EV-A71 remains poorly 21 understood. In mice, adaptation and virulence determinants have been mapped to mutations at 22 VP1-145, VP1-244 and VP2-149. We hypothesized that heparin-binding phenotype shapes 23 EV-A71 virulence in mice. We constructed six viruses with varying residues at VP1-98, VP1-24 145 (which are both heparin-binding determinants) and VP2-149 (based on the wild type 25 98E/145Q/149K, termed EQK) to generate KQK, KEK, EEK, EEI and EQI variants. We 26 demonstrated that the weak heparin-binder EEI was highly lethal in mice. The initially strong 27 heparin-binding EQI variant acquired an additional mutation VP1-K244E, which confers weak 28 heparin-binding phenotype resulting in elevated viremia and increased brain inflammation and 29 virus antigens in mice, with subsequent high virulence. EEI and EQI-K244E variants 30 inoculated into mice disseminated efficiently and displayed high viremia. Increasing 31 polymerase fidelity and impairing recombination of EQI attenuated virulence, suggesting the 32 importance of population diversity in EV-A71 pathogenesis in vivo. Combining in silico 33 docking and deep sequencing approaches, we inferred that virus population diversity is shaped 34 by electrostatic interactions at the five-fold axis of the virus surface. Electrostatic surface 35 charges facilitate virus adaptation by generating poor heparin-binding variants for better in vivo 36 dissemination in mice, likely due to reduced adsorption to heparin-rich peripheral tissues, 37 which ultimately results in increased neurovirulence. The dynamic switching from heparin-38 binding to weak heparin-binding phenotype in vivo explained the neurovirulence of EV-A71. 39 40 Author summary 41 Enterovirus A71 (EV-A71) is the primary cause of hand, foot and mouth disease, and it can 42 also infect the central nervous system and cause fatal outbreaks in young children. EV-A71 43 pathogenesis remains elusive. In this study, we demonstrated that EV-A71 variants with strong 44 affinity to heparan sulfate (heparin) have a growth advantage in tissue culture, but are 45 disadvantageous in vivo. When inoculated into mice, strong heparin-binding virus variants are 46 more likely to be adsorbed to peripheral tissues, resulting in impaired ability to disseminate 47 and being cleared from the bloodstream rapidly. The lower viremia level resulted in no 48 neuroinvasion. In contrast, weak heparin-binding variants show greater levels of viremia, 49 dissemination and subsequent neurovirulence in mice. We also provide evidence that the ability 50 of EV-A71 to bind heparin is mediated by electrostatic surface charges due to amino acids on 51 the virus capsid surface. In mice, EV-A71 undergoes adaptive mutation to acquire greater 52 negative surface charges, thus generating new virulent variants with weak heparin-binding 53 which allows greater viral spread. Our study underlines the...

show abstract

Section: Discussionmentioning

confidence: 90%

Electrostatic interactions at the five-fold axis alter heparin-binding phenotype and drive EV-A71 virulence in mice

Tee

Tan

Yogarajah

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…In fatal cases of EV-A71, the viral antigen was detected by histology within neurons and astrocytes (Yan et al, 2000;Yu et al, 2014). Similarly, post-mortem brain tissues from patients with confirmed EV-A71 infection and brain tissue from a non-human primate model of EV-A71 revealed that more than 80% of EV-A71 antigen was detected in astrocytes (Feng et al, 2016). As EV-D68 infected hiPSC derived astrocytes produced 2x more virus within 24 h post infection than 3 days post infection in neurons , it suggests that glia may be important for rapid viral propagation within the CNS.…”

Section: Cns Cell Types Susceptible To Enterovirusesmentioning

confidence: 95%

“…As EV-D68 infected hiPSC derived astrocytes produced 2x more virus within 24 h post infection than 3 days post infection in neurons , it suggests that glia may be important for rapid viral propagation within the CNS. Further in vitro functional studies identified that EV-A71 infected astrocyte cultures released pro-inflammatory cytokine IL-6 which increased secretion of excitatory neurotransmitters in bystander neurons that could have profound consequences on neuronal function (Feng et al, 2016) and immune response within the CNS. Collectively, this data highlights the important role astrocytes play in the development of neurological complications observed during EV infection.…”

Section: Cns Cell Types Susceptible To Enterovirusesmentioning

confidence: 99%

“…However, these neurons induce a cell cycle checkpoint arrest at G1/S phase and slowly die: a process called "abortive cell cycle re-entry" (Frade and Ovejero-Benito, 2015). The restrictive growth conditions within neurons likely contributes to the observed tissue tropism of EVs where EV-D68 can replicate in mature neurons but shows hindered viral growth while EV-A71 was preferentially detected within astrocytes (Feng et al, 2016).…”

Section: Host Factors Involved In Enterovirus Entry and Replicationmentioning

confidence: 99%

See 1 more Smart Citation

Molecular Pathogenicity of Enteroviruses Causing Neurological Disease

Majer¹,

McGreevy

Booth

2020

Front. Microbiol.

View full text Add to dashboard Cite

Enteroviruses are single-stranded positive-sense RNA viruses that primarily cause self-limiting gastrointestinal or respiratory illness. In some cases, these viruses can invade the central nervous system, causing life-threatening neurological diseases including encephalitis, meningitis and acute flaccid paralysis (AFP). As we near the global eradication of poliovirus, formerly the major cause of AFP, the number of AFP cases have not diminished implying a non-poliovirus etiology. As the number of enteroviruses linked with neurological disease is expanding, of which many had previously little clinical significance, these viruses are becoming increasingly important to public health. Our current understanding of these non-polio enteroviruses is limited, especially with regards to their neurovirulence. Elucidating the molecular pathogenesis of these viruses is paramount for the development of effective therapeutic strategies. This review summarizes the clinical diseases associated with neurotropic enteroviruses and discusses recent advances in the understanding of viral invasion of the central nervous system, cell tropism and molecular pathogenesis as it correlates with host responses.

show abstract

“…As a selective barrier, blood-brain barrier (BBB) protects central nervous system (CNS) from harmful pathogens in the blood. The access of EV-A71 into the CNS, except via retrograde axonal transport by nerves, most likely occurs through the BBB (Feng et al 2016). As a neurotropic virus, the mechanisms by which EV-A71 crossing the BBB and disseminating into brain parenchyma remain largely enigmatic (Denizot et al 2012).…”

Section: Introductionmentioning

confidence: 99%

Enterovirus A71 capsid protein VP1 increases blood–brain barrier permeability and virus receptor vimentin on the brain endothelial cells

et al. 2019

View full text Add to dashboard Cite

Enterovirus A71 (EV-A71) is the major cause of severe hand-foot-and-mouth diseases (HFMD), especially encephalitis and other nervous system diseases. EV-A71 capsid protein VP1 mediates virus attachment and is the important virulence factor in the EV-A71pathogenesis. In this study, we explored the roles of VP1 in the permeability of blood-brain barrier (BBB). Sera albumin, Evans blue, and dextran leaked into brain parenchyma of the 1-week-old C57BL/6J mice intracranially injected with VP1 recombinant protein. VP1 also increased the permeability of the brain endothelial cells monolayer, an in vitro BBB model. Tight junction protein claudin-5 was reduced in the brain tissues or brain endothelial cells treated with VP1. In contrast, VP1 increased the expression of virus receptor vimentin, which could be blocked with VP1 neutralization antibody. Vimentin expression in the VP1-treated brain endothelial cells was regulated by TGF-β/Smad-3 and NF-κB signal pathways. Moreover, vimentin over-expression was accompanied with compromised BBB. From these studies, we conclude that EV-A71 virus capsid protein VP1 disrupted BBB and increased virus receptor vimentin, which both may contribute to the virus entrance into brain and EV-A71 CNS infection.

show abstract

The Preferential Infection of Astrocytes by Enterovirus 71 Plays a Key Role in the Viral Neurogenic Pathogenesis

Cited by 32 publications

References 39 publications

Electrostatic interactions at the five-fold axis alter heparin-binding phenotype and drive EV-A71 virulence in mice

Electrostatic interactions at the five-fold axis alter heparin-binding phenotype and drive EV-A71 virulence in mice

Molecular Pathogenicity of Enteroviruses Causing Neurological Disease

Enterovirus A71 capsid protein VP1 increases blood–brain barrier permeability and virus receptor vimentin on the brain endothelial cells

Contact Info

Product

Resources

About