Virology, epidemiology, pathogenesis, and control of enterovirus 71

doi:10.1016/S1473-3099(10)70194-8

The Lancet Infectious Diseases

Volume 10, Issue 11, November 2010, Pages 778-790

https://doi.org/10.1016/S1473-3099(10)70194-8 Get rights and content

Summary

First isolated in California, USA, in 1969, enterovirus 71 (EV71) is a major public health issue across the Asia-Pacific region and beyond. The virus, which is closely related to polioviruses, mostly affects children and causes hand, foot, and mouth disease with neurological and systemic complications. Specific receptors for this virus are found on white blood cells, cells in the respiratory and gastrointestinal tract, and dendritic cells. Being an RNA virus, EV71 lacks a proofreading mechanism and is evolving rapidly, with new outbreaks occurring across Asia in regular cycles, and virus gene subgroups seem to differ in clinical epidemiological properties. The pathogenesis of the severe cardiopulmonary manifestations and the relative contributions of neurogenic pulmonary oedema, cardiac dysfunction, increased vascular permeability, and cytokine storm are controversial. Public health interventions to control outbreaks involve social distancing measures, but their effectiveness has not been fully assessed. Vaccines being developed include inactivated whole-virus, live attenuated, subviral particle, and DNA vaccines.

Introduction

Enteroviruses are small, single-stranded, positive-sense RNA viruses from the enterovirus genus in the family Picornaviridae.¹ They cause disorders with a wide range of clinical manifestations, including cutaneous, visceral, and neurological diseases. For many years polioviruses were the most important enteroviruses, since they led to large outbreaks of paralytic disease. A global campaign has, however, almost eradicated poliomyelitis from many regions worldwide. In its place, enterovirus 71 (EV71) causes major outbreaks of hand, foot, and mouth disease (HFMD), most frequently affecting children. This virus was first described in 1969,² although an analysis shows that EV71 was circulating in the Netherlands as early as 1963.³ Although present in most countries, the largest outbreaks of disease have been seen in the Asia-Pacific region, for reasons that are incompletely understood.4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 The neurological manifestations range from aseptic meningitis to acute flaccid paralysis and brainstem encephalitis, which is associated with systemic features, such as severe pulmonary oedema and shock, in many cases.17, 18 The clinical features, investigations, and management of severe EV71 disease are discussed in a companion article in The Lancet Neurology.¹⁹ In this Review we consider the virology, clinical and molecular epidemiology, pathogenesis, and prospects for control.

Section snippets

Classification

As well as the enterovirus genus, the large Picornaviridae family includes Rhinovirus spp (eg, the common cold), Hepatovirus spp (eg, human hepatitis A virus), Parechovirus spp (eg, human parechovirus 1 and 2), and two important animal virus genera, Cardiovirus spp (eg, encephalomyocarditis virus) and Aphthovirus spp (foot and mouth disease virus).¹ Human enteroviruses were traditionally separated into four classifications, according to their pathogenicity in human beings and experimental

Initial identification

EV71 was isolated from the stool of a child aged 9 months with encephalitis, in California, USA, in 1969,² although an earlier isolate has since been identified.³ Within 5 years small outbreaks of neurological infections, including encephalitis and aseptic meningitis, attributed to EV71 were reported in Australia, Japan, Sweden, and the USA.35, 36, 37, 38, 39

The dermotrophic properties of EV71 were first recognised when the virus caused epidemics of HFMD in Japan in 1973.38, 39 In the 1970s,

Gene groups, evolution, and geographical distribution

Phylogenetic analysis suggests that EV71 emerged from the coxsackievirus type A 16, as recently as 1940.³² The first complete phylogenetic analysis of EV71 based on the structural VP1 gene identified three independent lineages of EV71, designated A, B, and C;⁵³ each group has at least 15% divergence from the others. Group A consists of one member, the prototype BrCr strain, which was first identified in California, USA, in 1970, and was not reported outside the USA until 2008, when isolates

Viral determinants of virulence

The factors that determine whether EV71 infection will be asymptomatic or lead to HFMD or severe neurological disease are unknown. For polioviruses, the 5′ untranslated region and VP1 genes contain virulence determinants.²⁶ Several studies have, therefore, examined the relevant nucleotide sequences or the whole genome to compare isolates from fatal and non-fatal cases, but most isolates have been identical or nearly identical.81, 82 The frequency of CNS disease and other severe complications of

Virus entry and spread

EV71 is transmitted predominantly via the faeco-oral route, but can also spread through contact with virus-contaminated oral secretions, vesicular fluid, surfaces or fomites, and in respiratory droplets.¹ As with other enteroviruses, initial viral replication is presumed to occur in the lymphoid tissues of the oropharyngeal cavity (tonsils) and small bowel (Peyer's patches), with further multiplication in the regional lymph nodes (deep cervical and mesenteric nodes), giving rise to a mild

Surveillance and social distancing

The only measures available for disease control are public health approaches. Since early intervention can lessen the spread of the virus, many countries in the Asia-Pacific region, including Japan, Malaysia, Singapore, Taiwan, and Vietnam, have implemented heightened surveillance for EV71.15, 55, 56, 115, 116 HFMD has now become a notifiable disease in many countries in the region.¹¹⁶ However, since other enteroviruses, such as coxsackievirus types A 8, A 10, and A 16, can cause HFMD,

Conclusions

The increased size and frequency of EV71 outbreaks in the Asia-Pacific region over the past 12 years has been an important public health issue. Molecular epidemiological studies suggest that some viral genotypic subgroups seem to have massive potential for explosive epidemics, whereas others have more-indolent, low-level circulation. However, the biological determinants of these differences are poorly understood. The reasons for epidemiological differences between EV71 in the Asia-Pacific

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Inhibition of ESCRT-independent extracellular vesicles biogenesis suppresses enterovirus 71 replication and pathogenesis in mice
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Enterovirus 71 (EV71) causes hand-foot-and-mouth disease (HFMD), neurological complications, and even fatalities in infants. Clinically, the increase of extracellular vesicles (EVs) in EV71 patients' serum was highly associated with the severity of HFMD. EV71 boosts EVs biogenesis in an endosomal sorting complex required for transport (ESCRT)-dependent manner to facilitate viral replication. Yet, the impact of EVs-derived from ESCRT-independent pathway on EV71 replication and pathogenesis is highly concerned. Here, we assessed the effects of EV71-induced EVs from ESCRT-independent pathway on viral replication and pathogenesis by GW4869, a neutral sphingomyelinase inhibitor. Detailly, in EV71-infected mice, blockade of the biogenesis of tissue-derived EVs in the presence of GW4869 restored body weight loss, attenuated clinical scores, and improved survival rates. Furthermore, GW4869 dampens EVs biogenesis to reduce viral load and pathogenesis in multiple tissues of EV71-infected mice. Consistently, GW4869 treatment in a human intestinal epithelial HT29 cells decreased the biogenesis of EVs, in which the progeny EV71 particle was cloaked, leading to the reduction of viral infection and replication. Collectively, GW4869 inhibits EV71-induced EVs in an ESCRT-independent pathway and ultimately suppresses EV71 replication and pathogenesis. Our study provides a novel strategy for the development of therapeutic agents in the treatment for EV71-associated HFMD.
Effectiveness of enterovirus A71 vaccine against pediatric HFMD and disease profile of post-vaccination infection
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Vaccination has been proven effective against infection with enterovirus A71 (EV-A71) in clinical trials, but vaccine effectiveness in real-world situations remains incompletely understood. Furthermore, it is not clear whether previous vaccination will result in symptom attenuation among post-vaccinated cases.
Based on long-term data extracted from the only designed referral hospital for infectious diseases, we used a test-negative case-control design and multivariate logistic regression models to analyze the effectiveness of EV-A71 vaccine against hand, foot and mouth disease (HFMD). And then, generalized linear regression models were used to evaluate the associations between prior vaccination and disease profiles.
We selected 4883 inpatients for vaccine efficacy estimations and 2188 inpatients for disease profile comparisons. Vaccine effectiveness against EV-A71-induced HFMD for complete vaccination was 63.4 % and 51.7 % for partial vaccination. The vaccine effectiveness was higher among cases received the first dose within 12 months. No protection was observed against coxsackievirus (CV) A6-, CV-A10- or CV-A16-associated HFMD among children regardless of vaccination status. Completely vaccinated cases had shorter hospital stay and disease course compared to unvaccinated cases (P < 0.05).
These findings reiterate the need to continue the development of a multivalent vaccine or combined vaccines, and have implications for introducing optimized vaccination strategies.
Recent Advances in Enterovirus A71 Infection and Antiviral Agents
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Enterovirus A71 (EV-A71) is one of the major causative agents of hand, foot, and mouth disease (HFMD) that majorly affects children. Most of the time, HFMD is a mild disease but can progress to severe complications, such as meningitis, brain stem encephalitis, acute flaccid paralysis, and even death. HFMD caused by EV-A71 has emerged as an acutely infectious disease of highly pathogenic potential in the Asia-Pacific region. In this review, we introduced the properties and life cycle of EV-A71, and the pathogenesis and the pathophysiology of EV-A71 infection, including tissue tropism and host range of virus infection, the diseases caused by the virus, as well as the genes and host cell immune mechanisms of major diseases caused by enterovirus 71 (EV-A71) infection, such as encephalitis and neurologic pulmonary edema. At the same time, clinicopathologic characteristics of EV-A71 infection were introduced. There is currently no specific medication for EV-A71 infection, highlighting the urgency and significance of developing suitable anti–EV-A71 agents. This overview also summarizes the targets of existing anti–EV-A71 agents, including virus entry, translation, polyprotein processing, replication, assembly and release; interferons; interleukins; the mitogen-activated protein kinase, phosphatidylinositol 3-kinase, and protein kinase B signaling pathways; the oxidative stress pathway; the ubiquitin-proteasome system; and so on. Furthermore, it overviews the effects of natural products, monoclonal antibodies, and RNA interference against EV-A71. It also discusses issues limiting the research of antiviral drugs. This review is a systematic and comprehensive summary of the mechanism and pathological characteristics of EV-A71 infection, the latest progress of existing anti–EV-A71 agents. It would provide better understanding and guidance for the research and application of EV-A71 infection and antiviral inhibitors.
Advances in anti-EV-A71 drug development research
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Enterovirus A71 (EV-A71) is capable of causing hand, foot and mouth disease (HFMD), which may lead to neurological sequelae and even death. As EV-A71 is resistant to environmental changes and mutates easily, there is still a lack of effective treatments or globally available vaccines.
For more than 50 years since the HFMD epidemic, related drug research has been conducted. Progress in this area can promote the further application of existing potential drugs and develop more efficient and safe antiviral drugs, and provide useful reference for protecting the younger generation and maintaining public health security.
At present, researchers have identified hundreds of EV-A71 inhibitors based on screening repurposed drugs, targeted structural design, and rational modification of previously effective drugs as the main development strategies. This review systematically introduces the current potential drugs to inhibit EV-A71 infection, including viral inhibitors targeting key sites such as the viral capsid, RNA-dependent RNA polymerase (RdRp), 2C protein, internal ribosome entry site (IRES), 3C proteinase (3C^pro), and 2A proteinase (2A^pro), starting from each stage of the viral life cycle. Meanwhile, the progress of host-targeting antiviral drugs and their development are summarized in terms of regulating host immunity, inhibiting autophagy or apoptosis, and regulating the cellular redox environment. In addition, the current clinical methods for the prevention and treatment of HFMD are summarized and discussed with the aim of providing support and recommendations for the treatment of enterovirus infections including EV-A71.
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Peroxisomes are ubiquitous organelles found in eukaryotic cells that play a critical role in the oxidative metabolism of lipids and detoxification of reactive oxygen species (ROS). Recently, the role of peroxisomes in viral infections has been extensively studied. Although several studies have reported that peroxisomes exert antiviral activity, evidence indicates that viruses have also evolved diverse strategies to evade peroxisomal antiviral signals. In this review, we summarize the multiple roles of peroxisomes in the interplay between viruses and mammalian cells. Focus is given on the peroxisomal regulation of innate immune response, lipid metabolism, ROS production, and viral regulation of peroxisomal biosynthesis and degradation. Understanding the interactions between peroxisomes and viruses provides novel insights for the development of new antiviral strategies.
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Enteroviruses (EVs), which belong to the Picornaviridae family, infect individuals asymptomatically or cause mild symptoms (fever, runny nose, cough, skin rash, sneezing, mouth blister). Severe cases can cause various diseases, such as acute hemorrhagic conjunctivitis, aseptic meningitis, or myocarditis, especially in infants. These viruses can be transmitted via the fecal-oral route via contaminated water. In this study, we established a polymerase chain reaction (PCR) method for detecting EVs in water sample using Coxsackievirus B5 (CV-B5) and Echovirus 30 (E-30), which belong to species B of the four species of EVs (EV-A to D). Several methods have been investigated and compared for the detection of EVs, including real-time reverse transcription (RT) polymerase chain reaction and conventional RT-PCR. The most sensitive primer sets were selected, and the PCR conditions were modified to increase sensitivity. We also quantified the detection limits of real-time and conventional RT-PCR. The detection limits of conventional RT-PCR were detected in 10⁵–10⁶ copy/mL for CV-B5 and 10⁶–10⁷ copy/mL for E-30, respectively. This optimized method for detecting EVs is expected to contribute substantially to the investigation of EV outbreaks in water samples.

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ReviewVirology, epidemiology, pathogenesis, and control of enterovirus 71

Summary

Introduction

Section snippets

Classification

Initial identification

Gene groups, evolution, and geographical distribution

Viral determinants of virulence

Virus entry and spread

Surveillance and social distancing

Conclusions

Lancet

China J Clin Virol

Pediatr Neurol

Virol J

Lancet Neurol

Virus Res

Lancet

Virus Res

J Pediatr

Lancet

Virus Res

FEMS Microbiol

Vaccine

Clin Microbiol Infect

Virus Res

Mod Pathol

Trans R Soc Trop Med Hyg

Lancet

Enteroviruses: polioviruses, coxsackieviruses, echoviruses, and newer enteroviruses

An apparently new enterovirus isolated from patients with disease of the central nervous system

J Infect Dis

Epidemiology of enterovirus 71 in The Netherlands, 1963 to 2008

J Clin Microbiol

Epidemic hand, foot and mouth disease caused by human enterovirus 71, Singapore

Emerg Infect Dis

Deaths of children during an outbreak of hand, foot, and mouth disease in Sarawak, Malaysia: clinical and pathological characteristics of the disease

Clin Infect Dis

An epidemic of enterovirus 71 infection in Taiwan

N Engl J Med

Neurological manifestations of enterovirus 71 infection in children during an outbreak of hand, foot, and mouth disease in Western Australia

Clin Infect Dis

Epidemiologic and virologic investigation of hand, foot, and mouth disease, southern Vietnam, 2005

Emerg Infect Dis

Molecular epidemiology of human enterovirus 71 strains and recent outbreaks in the Asia-Pacific region: comparative analysis of the VP1 and VP4 genes

Emerg Infect Dis

Molecular epidemiology of enterovirus 71 infection in the Western Pacific Region

Pediatr Int

Epidemiologic features of hand-foot-mouth disease and herpangina caused by enterovirus 71 in Taiwan, 1998–2005

Pediatrics

Genetic analysis of the VP1 region of human enterovirus 71 strains isolated in Korea during 2000

Arch Virol

Neurologic complications in children with enterovirus 71 infection

N Engl J Med

Fulminant neurogenic pulmonary oedema with hand, foot, and mouth disease

Lancet

Basic rationale, current methods and future directions for molecular typing of human enterovirus

Expert Rev Mol Diagn

Complete genomic sequencing shows that polioviruses and members of human enterovirus species C are closely related in the noncapsid coding region

J Virol

Molecular detection and prevalence of enterovirus within environmental water in Taiwan

J Appl Microbiol

Prevalence of enteroviruses in hot spring recreation areas of Taiwan

FEMS Immunol Med Microbiol

Virucidal activity of Virkon S on human enterovirus

Med J Malaysia

Epidemics to eradication: the modern history of poliomyelitis

Virol J

Scavenger receptor B2 is a cellular receptor for enterovirus 71

Nat Med

Human P-selectin glycoprotein ligand-1 is a functional receptor for enterovirus 71

Nat Med

Sialylated glycans as receptor and inhibitor of enterovirus 71 infection to DLD-1 intestinal cells

Virol J

Enterovirus 71 infection of human dendritic cells

Exp Biol Med (Maywood)

DC-SIGN and immunoregulation

Cell Mol Immunol

Evolutionary genetics of human enterovirus 71: origin, population dynamics, natural selection, and seasonal periodicity of the VP1 gene

J Virol

Review
Virology, epidemiology, pathogenesis, and control of enterovirus 71