Displaying publications 1 - 20 of 83 in total

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  1. Tan SH, Ong KC, Perera D, Wong KT
    Antiviral Res, 2016 Aug;132:196-203.
    PMID: 27340013 DOI: 10.1016/j.antiviral.2016.04.015
    BACKGROUND: Enterovirus A71 (EV-A71) encephalomyelitis is an often fatal disease for which there is no specific treatment available. Passive immunization with a specific monoclonal antibody to EV-A71 was used on a murine model of EV-A71 encephalomyelitis to evaluate its therapeutic effectiveness before and after established central nervous system (CNS) infection.

    METHODS: Mice were intraperitoneally-infected with a mouse-adapted EV-A71 strain and treated with a dose of monoclonal antibody (MAb) daily for 3 days on day 1, 2 and 3 post-infection or for 3 days on 3, 4 and 5 post-infection. Treatment effectiveness was evaluated by signs of infection and survival rate. Histopathology and qPCR analyses were performed on mice sacrificed a day after completing treatment.

    RESULTS: In mock-treated mice, CNS infection was established from day 3 post-infection. All mice treated before established CNS infection, survived and recovered completely without CNS infection. All mice treated after established CNS infection survived with mild paralysis, and viral load and antigens/RNA at day 6 post-infection were significantly reduced.

    CONCLUSIONS: Passive immunization with our MAb could prevent CNS infection in mice if given early before the establishment of CNS infection. It could also ameliorate established CNS infection if optimal and repeated doses were given.

    Matched MeSH terms: Enterovirus Infections/drug therapy; Enterovirus Infections/immunology; Enterovirus Infections/mortality; Enterovirus Infections/virology*
  2. Tan DSK, Lee WS
    Med J Malaysia, 1981 Jun;36(2):76-8.
    PMID: 7343822
    Matched MeSH terms: Enterovirus Infections/microbiology*
  3. Bina Rai S, Wan Mansor H, Vasantha T, Norizah I, Chua KB
    Med J Malaysia, 2007 Aug;62(3):223-6.
    PMID: 18246912 MyJurnal
    Confinement homes are private institutions that provide full-time care for newborn babies and their respective postpartum mothers up to one month after delivery. An outbreak of fever and diarrhoea amongst newborns occurred in one such confinement home in Penang between the months of September to October 2004. An outbreak investigation was carried out including all babies, their respective mothers and workers in the home to determine the source of the outbreak and to institute control measures. Based on a working case definition of febrile illness with or without diarrhoea, 11 out of the 13 babies in the confinement home met the case definition. One hundred percent had symptoms of fever. 36.4% had symptoms of diarrhea and other respiratory conditions respectively. The attack rate of among babies in the confinement home was 90%. Echovirus 11 was isolated from 3 out of the 11 febrile cases. Echovirus 11 was isolated from the cerebrospinal fluid and stool of another baby at a private hospital that was epidemiologically linked to the first case. In conclusion, the outbreak of febrile illness amongst newborn babies in the affected confinement home was due to echovirus 11. The source was probably health-care associated with efficient transmission within the confinement home. The faecal-oral route was the most likely mode of transmission.
    Matched MeSH terms: Enterovirus Infections/epidemiology*; Enterovirus Infections/physiopathology; Enterovirus Infections/virology
  4. Lalani S, Gew LT, Poh CL
    Peptides, 2021 Feb;136:170443.
    PMID: 33171280 DOI: 10.1016/j.peptides.2020.170443
    The emergence of new and resistant viruses is a serious global burden. Conventional antiviral therapy with small molecules has led to the development of resistant mutants. In the case of hand, foot and mouth disease (HFMD), the absence of a US-FDA approved vaccine calls for urgent need to develop an antiviral that could serve as a safe, potent and robust therapy against the neurovirulent Enterovirus A71 (EV-A71). Natural peptides such as lactoferrin, melittin and synthetic peptides such as SP40, RGDS and LVLQTM have been studied against EV-A71 and have shown promising results as potent antivirals in pre-clinical studies. Peptides are considered safe, efficacious and pose fewer chances of resistance. Poor pharmacokinetic features of peptides can be overcome by the use of chemical modifications to improve in vivo delivery particularly by oral route. The use of nanotechnology can remarkably assist in the oral delivery of peptides and enhance stability in vivo. This can greatly increase patient compliance and make it more attractive as antiviral therapy.
    Matched MeSH terms: Enterovirus Infections
  5. Anasir MI, Zarif F, Poh CL
    J Biomed Sci, 2021 Jan 15;28(1):10.
    PMID: 33451326 DOI: 10.1186/s12929-021-00708-8
    Viruses from the genus Enterovirus (EV) of the Picornaviridae family are known to cause diseases such as hand foot and mouth disease (HFMD), respiratory diseases, encephalitis and myocarditis. The capsid of EV is an attractive target for the development of direct-acting small molecules that can interfere with viral entry. Some of the capsid binders have been evaluated in clinical trials but the majority have failed due to insufficient efficacy or unacceptable off-target effects. Furthermore, most of the capsid binders exhibited a low barrier to resistance. Alternatively, host-targeting inhibitors such as peptides derived from the capsid of EV that can recognize cellular receptors have been identified. However, the majority of these peptides displayed low anti-EV potency (µM range) as compared to the potency of small molecule compounds (nM range). Nonetheless, the development of anti-EV peptides is warranted as they may complement the small-molecules in a drug combination strategy to treat EVs. Lastly, structure-based approach to design antiviral peptides should be utilized to unearth potent anti-EV peptides.
    Matched MeSH terms: Enterovirus Infections/drug therapy*; Enterovirus Infections/virology
  6. Teng CL, Zuhanariah MN, Ng CS, Goh CC
    Med J Malaysia, 2014 Aug;69 Suppl A:4-7.
    PMID: 25417946
    This article describes the methodology of this bibliography. A search was conducted on the following: (1) bibliographic databases (PubMed, Scopus, and other databases) using search terms that maximize the retrieval of Malaysian publications; (2) Individual journal search of Malaysian healthrelated journals; (3) A targeted search of Google and Google Scholar; (4) Searching of Malaysian institutional repositories; (5) Searching of Ministry of Health and Clinical Research Centre website. The publication years were limited to 2000- 2013. The citations were imported or manually entered into bibliographic software Refworks. After removing duplicates, and correcting data entry errors, PubMed's Medical Subject Headings (MeSH terms) were added. Clinical research is coded using the definition "patient-oriented-research or research conducted with human subjects (or on material of human origin) for which the investigator directly interacts with the human subjects at some point during the study." A bibliography of citations [n=2056] that fit the criteria of clinical research in Malaysia in selected topics within five domains was generated: Cancers [589], Cardiovascular diseases [432], Infections [795], Injuries [142], and Mental Health [582]. This is done by retrieving citations with the appropriate MESH terms, as follow: For cancers (Breast Neoplasms; Colorectal Neoplasms; Uterine Cervical Neoplasms), for cardiovascular diseases (Coronary Disease; Hypertension; Stroke), for infections (Dengue; Enterovirus Infections, HIV Infections; Malaria; Nipah Virus; Tuberculosis), for injuries (Accidents, Occupational; Accidents, Traffic; Child Abuse; Occupational Injuries), for mental health (Depression; Depressive Disorder; Depressive Disorder, Major; Drug Users; Psychotic Disorders; Suicide; Suicide, Attempted; Suicidal Ideation; Substance- Related Disorders).
    Matched MeSH terms: Enterovirus Infections
  7. Khairul AH, Chem YK, Keniscope C, Rosli J, Hassan S, Mat J, et al.
    Malays J Pathol, 2010 Jun;32(1):49-52.
    PMID: 20614726 MyJurnal
    In the past decade, enterovirus 71 (EV71) and chikungunya (CHIK) virus have re-emerged periodically causing serious public health problems in Malaysia, since their first emergence in 1997 and 1998 respectively. This study demonstrates that CHIK virus causes similar patterns of cytopathic effect in cultured Vero cells as some enteroviruses. They also show positive cross-reaction on direct immunofluorescence staining using monoclonal antibodies meant for typing enteroviruses. Without adequate clinical and epidemiological information for correlation, CHIK virus isolated from patients with acute febrile rash can be wrongly reported as untypeable enterovirus due to its cross-reactivity with commercial pan-enterovirus monoclonal antibodies. This is due to the diagnostic laboratory being unaware of such cross-reactions as it has not been reported previously. Final identification of the virus could be determined with specific antibodies or molecular typing using specific oligonucleotide primers for the CHIK virus.
    Matched MeSH terms: Enterovirus Infections/diagnosis*
  8. Lin JY, Shih SR
    J Biomed Sci, 2014;21:18.
    PMID: 24602216 DOI: 10.1186/1423-0127-21-18
    Enterovirus 71 (EV71) is a member of Picornaviridae that causes mild and self-limiting hand, foot, and mouth disease (HFMD). However, EV71 infections can progress to polio-like paralysis, neurogenic pulmonary edema, and fatal encephalitis in infants and young children. Large EV71 outbreaks have been reported in Taiwan, China, Japan, Malaysia, Singapore, and Australia. This virus is considered a critical emerging public health threat. EV71 is an important crucial neurotropic enterovirus for which there is currently no effective antiviral drug or vaccine. The mechanism by which EV71 causes severe central nervous system complications remains unclear. The interaction between the virus and the host is vital for viral replication, virulence, and pathogenicity. SCARB2 or PSGL-1 receptor binding is the first step in the development of viral infections, and viral factors (e.g., 5' UTR, VP1, 3C, 3D, 3' UTR), host factors and environments (e.g., ITAFs, type I IFN) are also involved in viral infections. The tissue tropism and pathogenesis of viruses are determined by a combination of several factors. This review article provides a summary of host and virus factors affecting cell and tissue tropism and the pathogenesis of enteroviruses.
    Matched MeSH terms: Enterovirus Infections/genetics; Enterovirus Infections/epidemiology*; Enterovirus Infections/virology
  9. Mandary MB, Masomian M, Ong SK, Poh CL
    Viruses, 2020 Jun 17;12(6).
    PMID: 32560288 DOI: 10.3390/v12060651
    Viral plaque morphologies in human cell lines are markers for growth capability and they have been used to assess the viral fitness and selection of attenuated mutants for live-attenuated vaccine development. In this study, we investigate whether the naturally occurring plaque size variation reflects the virulence of the variants of EV-A71. Variants of two different plaque sizes (big and small) from EV-A71 sub-genotype B4 strain 41 were characterized. The plaque variants displayed different in vitro growth kinetics compared to the parental wild type. The plaque variants showed specific mutations being present in each variant strain. The big plaque variants showed four mutations I97L, N104S, S246P and N282D in the VP1 while the small plaque variants showed I97T, N237T and T292A in the VP1. No other mutations were detected in the whole genome of the two variants. The variants showed stable homogenous small plaques and big plaques, respectively, when re-infected in rhabdomyosarcoma (RD) and Vero cells. The parental strain showed faster growth kinetics and had higher viral RNA copy number than both the big and small plaque variants. Homology modelling shows that both plaque variants have differences in the structure of the VP1 protein due to the presence of unique spontaneous mutations found in each plaque variant This study suggests that the EV-A71 sub-genotype B4 strain 41 has at least two variants with different plaque morphologies. These differences were likely due to the presence of spontaneous mutations that are unique to each of the plaque variants. The ability to maintain the respective plaque morphology upon passaging indicates the presence of quasi-species in the parental population.
    Matched MeSH terms: Enterovirus Infections/virology*
  10. de Azevedo JP, Nascimento LR, Cortinovis MC, Oliveira SS, da Costa EV, da Silva EE
    J Clin Virol, 2004 Dec;31(4):248-52.
    PMID: 15494264 DOI: 10.1016/j.jcv.2004.04.007
    BACKGROUND: Human adenoviruses are classified into six species, A-F, and 51 serotypes are recognized. Adenoviruses can cause a broad range of diseases. Serotypes 3, 7 and 21 are most commonly associated with CNS disease. Serotype 21 (specie B) was isolated from brain tissue and CSF of patients with acute flaccid paralysis (AFP) in Malaysia.
    OBJECTIVES: Characterize, by molecular methods, species B adenoviruses isolated from poliomyelitis-suspected cases and investigate the possible etiological role of adenoviruses in acute flaccid paralysis (AFP).
    STUDY DESIGN: 622 virus isolates, including Sabin-related polioviruses, non-polio enteroviruses (NPEV) and adenoviruses, were recovered from fecal specimens in our laboratory during the period of 1997-2002 from AFP cases occurring in Brazil, Peru and Bolivia. Negative controls consisted of 528 fecal specimens collected from healthy children <==5 of age. Of these, 478 were contacts of AFP negative cases and 50 were from a day-care center.
    RESULTS: Sixty-four adenovirus strains isolated in HEp2 (human laryngeal tumor cells) cells were confirmed as such by an adenovirus-group specific PCR. Nucleotide sequencing identified the following adenovirus species: A (3 isolates), B (20 isolates), C (38 isolates), D (2 isolates) and E (1 isolate). The following serotypes belonging to the species B were identified: Ad3 (1 strain), Ad7 (17 strains) and, Ad16 (2 strains).
    CONCLUSION: Other viral agents became more recognized in association with CNS diseases in areas where wild polioviruses have been eradicated. The possible role of species B adenoviruses in the etiology of AFP cases similar to that caused by wild poliovirus is discussed.
    Matched MeSH terms: Enterovirus Infections/epidemiology; Enterovirus Infections/virology*
  11. Chan YF, Wee KL, Chiam CW, Khor CS, Chan SY, Amalina W MZ, et al.
    Trop Biomed, 2012 Sep;29(3):451-66.
    PMID: 23018509 MyJurnal
    Three genomic regions, VP4 capsid, VP1 capsid and 3D RNA polymerase of human enterovirus 71 (EV-71) and coxsackievirus A16 (CV-A16) were sequenced to understand the evolution of these viruses in Malaysia. A total of 42 EV-71 and 36 CV-A16 isolates from 1997- 2008 were sequenced. Despite the presence of many EV-71 subgenotypes worldwide, only subgenotypes B3, B4, B5, C1 and C2 were present in Malaysia. Importation of other subgenotypes such as C3, C4/D and C5 from other countries was infrequent. For CV-A16, the earlier subgenotype B1 was replaced by subgenotypes B2a and the recent B2c. Subgenotype B2a was present throughout the study while B2c only emerged in 2005. No genetic signatures could be attributed to viral virulence suggesting that host factors have a major role in determining the outcome of infection. Only three EV-71 B3 isolates showed non-consistent phylogeny in the 3D RNA polymerase region which indicated occurrence of recombination in EV-71. High genetic diversity was observed in the Malaysian EV-71 but Malaysian CV-A16 showed low genetic diversity in the three genomic regions sequenced. EV-71 showed strong purifying selection, but that occurred to a lesser extent in CV-A16.
    Matched MeSH terms: Enterovirus Infections/epidemiology; Enterovirus Infections/virology*
  12. Chua BH, McMinn PC, Lam SK, Chua KB
    J Gen Virol, 2001 Nov;82(Pt 11):2629-39.
    PMID: 11602774
    The complete nucleotide sequences are reported of two strains of echovirus 7, the prototype Wallace strain (Eo7-Wallace) and a recent Malaysian strain isolated from the cerebrospinal fluid of a child with fatal encephalomyelitis (Eo7-UMMC strain). The molecular findings corroborate the serological placement of the UMMC strain as echovirus 7. Both Eo7-Wallace and Eo7-UMMC belong to the species human enterovirus B and are most closely related to echovirus 11. Eo7-UMMC has undergone significant genetic drift from the prototype strain in the 47 years that separate the isolation of the two viruses. Phylogenetic analysis revealed that Eo7-UMMC did not arise from recombination with another enterovirus serotype. The molecular basis for the severely neurovirulent phenotype of Eo7-UMMC remains unknown. However, it is shown that mutations in the nucleotide sequence of the 5' untranslated region (UTR) of Eo7-UMMC result in changes to the putative structure of the 5' UTR. It is possible that these changes contribute to the neurovirulence of Eo7-UMMC.
    Matched MeSH terms: Enterovirus Infections/virology*
  13. Singh S, Poh CL, Chow VT
    Microbiol. Immunol., 2002;46(11):801-8.
    PMID: 12516778
    Enterovirus 71 (EV71) is a major aetiological agent of hand, foot and mouth disease (HFMD). In recent years, several outbreaks in East Asia were associated with neurological complications and numerous deaths. An outbreak in Singapore in October 2000 afflicted thousands of children, resulting in four fatal cases from three of whom EV71 was isolated. The genomes of two representative EV71 strains isolated from a fatal case and a surviving patient were completely sequenced, and their nucleotide and amino acid sequences compared with known EV71 strains. The two outbreak strains were classified under genogroup B, together with those previously isolated in Singapore, Malaysia and Japan. Comparative sequence analysis of the two Singapore strains revealed 99% nucleotide similarity, while their deduced amino acid sequences were almost identical except for residue 1506 in the 3A non-structural region. Given that the outbreak involved closely related genetic variants of EV71, the broad spectrum of disease severity may be attributed to critical factors such as varying viral inoculation doses or differing host immune responses following infection, but is less likely to be due to the emergence of EV71 strains with heightened virulence.
    Matched MeSH terms: Enterovirus Infections/mortality; Enterovirus Infections/epidemiology*; Enterovirus Infections/virology
  14. Kuan CS, Yew SM, Hooi PS, Lee LM, Ng KP
    Malays J Med Sci, 2017 Oct;24(5):33-43.
    PMID: 29386970 MyJurnal DOI: 10.21315/mjms2017.24.5.4
    Introduction: Acute respiratory tract infections (ARTIs) are a major cause of morbidity and mortality in paediatric patients. Therefore, early detection of the viral aetiologies of ARTIs is essential for patient management and infection control. In this study, we evaluated the performance of a new multiplex polymerase chain reaction (PCR) assay (xTAG Respiratory Viral Panel [RVP] Fast v2) in the detection of respiratory viruses by comparing it with that of viral culture and direct immunofluorescence (IF) staining.

    Methods: Nasopharyngeal swab and aspirate samples were collected prospectively from 199 patients who presented with ARTIs at the University Malaya Medical Centre (UMMC) in Kuala Lumpur, Malaysia during a 10-month period. The PCR assay was conducted in parallel with conventional culture and direct IF staining methods.

    Results: The positive rate of the xTAG RVP Fast v2 assay (78.4%) in detecting respiratory viruses was higher than that of the viral isolation (7.5%) and direct IF (23.1%) methods. Using the xTAG RVP Fast v2 assay, human enterovirus/human rhinovirus (HEV/HRV) was the most frequently detected (46.2%). The xTAG RVP Fast v2 assay revealed mixed infection caused by two or three respiratory viruses in 40 specimens, and these were undetected by the viral isolation and direct IF methods.

    Conclusion: The xTAG RVP Fast v2 assay was superior to conventional methods in the identification of common respiratory viruses, with higher sensitivity and shorter turnaround times for laboratory results.

    Matched MeSH terms: Enterovirus Infections
  15. Poh CL, Tan EL
    Methods Mol Biol, 2011;665:65-77.
    PMID: 21116796 DOI: 10.1007/978-1-60761-817-1_5
    Enteroviruses are positive stranded RNA viruses belonging to the genus Enterovirus of the Picornaviridae family. Human enteroviruses are transmitted through the fecal-oral route and have been shown to cause mild to life-threatening diseases. Various diagnostic methods have been developed to detect enteroviruses from clinical specimens but many were impeded by requirements for special reagents, lengthy procedures, low sensitivity or cross-reactivity. This chapter describes rapid and highly sensitive methods of enteroviral detection directly from clinical specimens based on a conventional one-step Reverse Transcription polymerase chain reaction (RT-PCR) and a one-step real-time RT-PCR.
    Matched MeSH terms: Enterovirus Infections/diagnosis*
  16. Lee MS, Chang LY
    Expert Rev Vaccines, 2010 Feb;9(2):149-56.
    PMID: 20109026 DOI: 10.1586/erv.09.152
    Enterovirus 71 (EV71) was first isolated in 1969 in California, USA. Several epidemic outbreaks with high mortality rates have occurred in European and Asian Countries (Bulgaria in 1975, Hungary in 1978, Malaysia in 1997, Taiwan in 1998 and China in 2008). EV71 CNS involvement may be associated with neurological sequelae, delayed neurodevelopment and reduced cognitive functioning. Since poliovirus was nearly eradicated by vaccination, EV71 is now considered as one of the top candidates for new vaccine development against human enteroviruses. Recently, several EV71 vaccine candidates, including live-attenuated virus, inactivated whole virus, recombinant viral protein, virus-like particle and DNA vaccines, have been evaluated in animals but no clinical trial has yet been conducted. Based on historical experiences with poliovirus vaccines and animal studies, the inactivated whole-virus vaccines are feasible and could be licensed readily, so these are targeted for preparing clinical trials in several organizations in Asia.
    Matched MeSH terms: Enterovirus Infections/epidemiology; Enterovirus Infections/prevention & control*
  17. Lum LC, Chua KB, McMinn PC, Goh AY, Muridan R, Sarji SA, et al.
    J Clin Virol, 2002 Jan;23(3):153-60.
    PMID: 11595594
    Hand, foot, and mouth disease (HFMD) is endemic in Malaysia. In 1997, a large outbreak of enterovirus 71 (EV-71) associated HFMD resulted in 41 deaths due to severe left ventricular dysfunction and central nervous system infection with extensive damage to the medulla and pons. The clinical presentation in all these patients were rapid cardio-respiratory decompensation leading to cardiac arrest. Another large outbreak of HFMD with 55 fatal cases and a similar clinical picture was reported in Taiwan in 1998. In 2000, an outbreak of HFMD resulted in the deaths of three children who had rapid cardio-respiratory decompensation and one child who survived a central nervous system infection.
    Matched MeSH terms: Enterovirus Infections/blood; Enterovirus Infections/virology*
  18. Manisya Zauri Abdul Wahid, Tengku Rogayah T. Abd. Rashid, Hariyati Md. Ali, Hamadah Mohd Shafiff, Mohd. Shamsul Samsuddin, Syarifah Nur Aisyatun Syed Mohd Salleh, et al.
    MyJurnal
    Introduction:Echoviruses are Enteroviruses (HEVs) that infect millions of people annually worldwide, primarily paediatrics. These viruses are frequently associated with outbreaks and sporadic cases of viral meningitis, enceph-alitis, paralysis, myocarditis, severe systemic infections; and hand-foot-mouth disease. This study is a retrospective study to identify Echovirus serotypes circulating in Malaysia from January 2014 to June 2019, and their roles in outbreak prediction. This study investigated the Echovirus serotypes circulating in Malaysia from January 2014 to June 2019. Methods: A total of 13,855 inpatient samples consisting respiratory secretion, stool, tissue and body fluid from around the country were received by the Virology Unit, Institute for Medical Research between January 2014 and June 2019. The presence of HEV’s RNA was detected by qPCR. The identified positive sample was further isolated by cell culture and identified by Immunofluorescence Assay (IFA). The IFA positive samples were subjected to amplification of partial VP4 gene by RT-PCR, and proceeded to Sanger sequencing for phylogenetic analysis by using ChromasPro and MEGA Software. The sequence generated were analysed by BLAST to confirm the sequence serotypes generated. Results: Echovirus genome was detected in 0.35% (37/10,681) of the patients. The circulating Echovirus subtypes in Malaysia between January 2014 and June 2019 were Echo-11 (43.2%; 16/37), followed by Echo-6 (16.2%; 6/37); 8.1% (3/37) of Echo-7 and Echo-13, respectively. Meanwhile, other types of Echoviruses (24.3%; 9/37) such as Echo 3-5, Echo-14, Echo-16, Echo-18, Echo-25 and Echo-30 were also detected in this study. Conclusion: In this study, it has been found that Echovirus 11 serotype is the most predominant Echovirus serotype circulating in Malaysia between January 2014 and June 2019. It has been reported to cause severe diseases, such as aseptic meningitis. Therefore, the identification of circulating serotypes of Echovirus is critical to predict the Echovi-rus outbreak and to reduce the risk of developing severe disease in Malaysia.
    Matched MeSH terms: Enterovirus Infections
  19. Tee HK, Tan CW, Yogarajah T, Lee MHP, Chai HJ, Hanapi NA, et al.
    PLoS Pathog, 2019 11;15(11):e1007863.
    PMID: 31730673 DOI: 10.1371/journal.ppat.1007863
    Enterovirus A71 (EV-A71) causes hand, foot and mouth disease epidemics with neurological complications and fatalities. However, the neuropathogenesis of EV-A71 remains poorly understood. In mice, adaptation and virulence determinants have been mapped to mutations at VP2-149, VP1-145 and VP1-244. We investigate how these amino acids alter heparin-binding phenotype and shapes EV-A71 virulence in one-day old mice. We constructed six viruses with varying residues at VP1-98, VP1-145 (which are both heparin-binding determinants) and VP2-149 (based on the wild type 149K/98E/145Q, termed KEQ) to generate KKQ, KKE, KEE, IEE and IEQ variants. We demonstrated that the weak heparin-binder IEE was highly lethal in mice. The initially strong heparin-binding IEQ variant acquired an additional mutation VP1-K244E, which confers weak heparin-binding phenotype resulting in elevated viremia and increased virus antigens in mice brain, with subsequent high virulence. IEE and IEQ-244E variants inoculated into mice disseminated efficiently and displayed high viremia. Increasing polymerase fidelity and impairing recombination of IEQ attenuated the virulence, suggesting the importance of population diversity in EV-A71 pathogenesis in vivo. Combining in silico docking and deep sequencing approaches, we inferred that virus population diversity is shaped by electrostatic interactions at the five-fold axis of the virus surface. Electrostatic surface charges facilitate virus adaptation by generating poor heparin-binding variants for better in vivo dissemination in mice, likely due to reduced adsorption to heparin-rich peripheral tissues, which ultimately results in increased neurovirulence. The dynamic switching between heparin-binding and weak heparin-binding phenotype in vivo explained the neurovirulence of EV-A71.
    Matched MeSH terms: Enterovirus Infections/metabolism; Enterovirus Infections/epidemiology; Enterovirus Infections/virology*
  20. Wong KT
    Neuropathol. Appl. Neurobiol., 2000 Aug;26(4):313-8.
    PMID: 10931364
    Two major epidemics of viral encephalitis occurred in Asia in 1997 and 1998. The first was a re-emergence of neurovirulent strains of enterovirus 71, which caused severe encephalomyelitis in children in Malaysia, Taiwan and Japan, on a background of hand, foot and mouth disease. Necropsy studies of patients who died of enterovirus 71 infection showed severe perivascular cuffing, parenchymal inflammation and neuronophagia in the spinal cord, brainstem and diencephalon, and in focal areas in the cerebellum and cerebrum. Although no viral inclusions were detected, immunohistochemistry showed viral antigen in the neuronal cytoplasm. Inflammation was often more extensive than neuronal infection, suggesting that other factors, in addition to direct viral cytolysis, may be involved in tissue damage. The second epidemic of viral encephalitis was the result of a novel paramyxovirus called Nipah, which mainly involved pig handlers in Malaysia and Singapore. Pathological evidence suggested that the endothelium of small blood vessels in the central nervous system was particularly susceptible to infection. This led to disseminated endothelial damage and syncytium formation, vasculitis, thrombosis, ischaemia and microinfarction. However, there was also evidence of neuronal infection by the virus and this may also have contributed to the neurological dysfunction in Nipah encephalitis. Some patients who seemed to recover from the acute symptoms have been re-admitted with clinical findings suggestive of relapsing encephalitis. As these two epidemics indicate, the emergence and re-emergence of viral encephalitides continue to pose considerable challenges to the neuropathologist, in establishing the diagnosis and unravelling the pathogenesis of the neurological disease.
    Matched MeSH terms: Enterovirus Infections/epidemiology*; Enterovirus Infections/pathology; Enterovirus Infections/virology*
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