Recent advances in the understanding of enterovirus A71 infection: a focus on neuropathogenesis

ABSTRACT

Introduction: Hand, foot, and mouth disease caused by enterovirus A71 (EV-A71) is more frequently associated with neurological complications and deaths compared to other enteroviruses.

Areas covered: The authors discuss current understanding of the neuropathogenesis of EV-A71 based on various clinical, human, and animal model studies. The authors discuss the important advancements in virus entry, virus dissemination, and neuroinvasion. The authors highlight the role of host immune system, host genetic factors, viral quasispecies, and heparan sulfate in EV-A71 neuropathogenesis.

Expert opinion: Comparison of EV-A71 with EV-D68 and PV shows similarity in primary target sites and dissemination to the central nervous system. More research is needed to understand cellular tropisms, persistence of EV-A71, and other possible invasion routes. EV-A71 infection has varied clinical manifestations which may be attributed to multiple receptors usage. Future development of antivirals and vaccines should target neurotropic enteroviruses. Repurposing drug and immunomodulators used in combination could reduce the severity of EV-A71 infection. Only a few drugs have been tested in clinical trials, and in the absence of antiviral and vaccines (except China), active virus surveillance, good hand hygiene, and physical distancing should be advocated. A better understanding of EV-A71 neuropathogenesis is critical for antiviral and multivalent vaccines development.

KEYWORDS:

• Enterovirus A71
• enterovirus
• neuropathogenesis
• receptor
• heparan sulfate
• SCARB2
• antiviral

Article highlights

• Children under 5 years old are at greatest risk of severe EV-A71 infections involving the central nervous system.

• EV-A71 utilizes multiple attachment receptors. The role of more well-studied receptors such as SCARB2, PSGL-1, and heparan sulfate in the EV-A71 neuropathogenesis are highlighted.

• High viremia is crucial for virus dissemination to other secondary target tissues such as the brain.

• Retrograde axonal transport is proposed as the major neuroinvasion route for EV-A71.

• Host factors, especially the innate arm of immune responses, are important barriers to EV-A71 infection.

• Gene polymorphisms in innate immunity genes are associated with severe EV-A71 infection.

• The dynamics of viral quasispecies influence EV-A71 neurovirulence.

• Heparan sulfate in vascular rich tissues and innate immune responses play important roles in blocking virus dissemination.

• Strong evidence from other neurotropic viruses supports the role of heparan sulfate in neurovirulence.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This study was supported in part by grants from the Ministry of Higher Education, Malaysia (Fundamental Research Grant Scheme FRGS/1/2018/SKK11/UM/02/2) and Newton Advanced Fellowship [XR057] granted to YFC.