Displaying publications 1 - 20 of 83 in total

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  1. Characterization of species B adenoviruses isolated from fecal specimens taken from poliomyelitis-suspected cases
    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*
  2. Enterovirus A71 and coxsackievirus A16 show different replication kinetics in human neuronal and non-neuronal cell lines
    Yogarajah T, Ong KC, Perera D, Wong KT
    Arch Virol, 2017 Mar;162(3):727-737.
    PMID: 27878462 DOI: 10.1007/s00705-016-3157-4
    Enterovirus A71 (EV-A71) and coxsackievirus A16 (CV-A16) are closely related enteroviruses that cause hand, foot and mouth disease (HFMD) in children. Serious neurological complications almost always occur in EV-A71 infection, but are rare in CV-A16 infection. Based on the hypothesis that this may be because EV-A71 infects neuronal cells more easily than CV-A16, we compared virus infection, replication and spread of EV-A71 and CV-A16 in SK-N-SH cells. We found that CV-A16 invariably showed significantly lower replication and caused less necrotic cell death in SK-N-SH cells, compared with EV-A71. This was not due to a lower proportion of CV-A16-infected cells, since both viruses showed similar proportions of infected cells at all time points analyzed. Furthermore, reduced replication of CV-A16 in SK-N-SH cells does not appear to be due to limited viral receptor availability, which might limit viral entry, because experiments with viral RNA-transfected cells showed the same results as for live virus infections. On the other hand, no differences were observed between EV-A71 and CV-A16 in RD cells and results were generally similar in RD cells for both viruses. Taken together, our findings suggest that the poor growth of CV-A16 and EV-A71in SK-N-SH cells, compared with RD cells, may be due to cell type-specific restrictions on viral replication and spread. Furthermore, the lower viral replication and necrotic cell death in CV-A16-infected SK-N-SH cells, compared with EV-A71-infected SK-N-SH cells, is consistent with the lower prevalence of neurotropism observed in CV-A16-associated HFMD outbreaks. Nonetheless, in vivo data and more extensive comparisons of different viral strains are essential to confirm our findings.
    Matched MeSH terms: Enterovirus Infections
  3. Impact of genetic changes, pathogenicity and antigenicity on Enterovirus- A71 vaccine development
    Yee PTI, Laa Poh C
    Virology, 2017 06;506:121-129.
    PMID: 28384566 DOI: 10.1016/j.virol.2017.03.017
    Enterovirus-A71 (EV-A71) is an etiological agent of the hand, foot and mouth disease (HFMD). EV-A71 infection produces high fever and ulcers in children. Some EV-A71 strains produce severe infections leading to pulmonary edema and death. Although the protective efficacy of the inactivated vaccine (IV) was ≥90% against mild HFMD, there was approximately 80% protection against severe HFMD. The monovalent EV-A71 IV elicits humoral immunity but lacks long-term immunogenicity. Spontaneous mutations of the EV-A71 genome could lead to antigenicity changes and the virus may not be neutralized by antibodies elicited by the IV. A better alternative would be the live attenuated vaccine (LAV) that elicits cellular and humoral immunity. The LAV induces excellent antigenicity and chances of reversion is reduced by presence of multiple mutations which could reduce pathogenicity. Besides CV-A16, outbreaks have been caused by CV-A6 and CV-A10, hence the development of bivalent and trivalent vaccines is required.
    Matched MeSH terms: Enterovirus Infections/immunology; Enterovirus Infections/prevention & control*; Enterovirus Infections/virology
  4. Fulltext T Cell Immunity To Enterovirus 71 Infection In Humans And Implications For Vaccine Development
    Yee PTI, Poh CL
    Int J Med Sci, 2018;15(11):1143-1152.
    PMID: 30123051 DOI: 10.7150/ijms.26450
    Enterovirus 71 (EV-A71) is one of the major pathogens causing hand, foot and mouth disease (HFMD). Some strains can lead to neurological disease and fatality in children. Up to date, there is no FDA-approved vaccine to prevent severe HFMD and mortality. Although the inactivated vaccine has advanced to production in China, lack of long-term protection and the requirement of multiple boosters have necessitated the development of other types of vaccines. Recent studies indicate that cellular and not humoral immunity determines the clinical outcome of EV-A71 infections. High levels of cytokines such as IL-1β, IL-6, IL-10 and IFN-γ tend to correlate with clinical severity in patients with pulmonary edema and encephalitis. The live attenuated vaccine may serve as the preferred choice as it can induce excellent humoral and cellular immunity as well as live-long immunity. Expression of certain HLA alleles such as TNF-α promoter type II (-308 allele), HLA-A33 and HLA-DR17 responses have been linked to severe HFMD. However, the high variability of MHC genes could restrict T cell recognition and be a major obstacle in the design of peptide vaccines. Hence, the development of a T cell universal vaccine (incorporating both CD4+ and CD8+ T cell epitopes) that induces broad, multifunctional and cross-reactive CD8+ T cell responses maybe desirable.
    Matched MeSH terms: Enterovirus Infections/immunology*
  5. Fulltext Molecular epidemiology of enterovirus 71 infection in the central region of Taiwan from 2002 to 2012
    Wu WH, Kuo TC, Lin YT, Huang SW, Liu HF, Wang J, et al.
    PLoS One, 2013;8(12):e83711.
    PMID: 24391812 DOI: 10.1371/journal.pone.0083711
    Enterovirus 71 (EV71), a causative agent of hand, foot, and mouth disease can be classified into three genotypes and many subtypes. The objectives of this study were to conduct a molecular epidemiological study of EV71 in the central region of Taiwan from 2002-2012 and to test the hypothesis that whether the alternative appearance of different EV71 subtypes in Taiwan is due to transmission from neighboring countries or from re-emergence of pre-existing local strains. We selected 174 EV71 isolates and used reverse transcription-polymerase chain reaction to amplify their VP1 region for DNA sequencing. Phylogenetic analyses were conducted using Neighbor-Joining, Maximum Likelihood and Bayesian methods. We found that the major subtypes of EV71 in Taiwan were B4 for 2002 epidemic, C4 for 2004-2005 epidemic, B5 for 2008-2009 epidemic, C4 for 2010 epidemic and B5 for 2011-2012 epidemic. Phylogenetic analysis demonstrated that the 2002 and 2008 epidemics were associated with EV71 from Malaysia and Singapore; while both 2010 and 2011-2012 epidemics originated from different regions of mainland China including Shanghai, Henan, Xiamen and Gong-Dong. Furthermore, minor strains have been identified in each epidemic and some of them were correlated with the subsequent outbreaks. Therefore, the EV71 infection in Taiwan may originate from pre-existing minor strains or from other regions in Asia including mainland China. In addition, 101 EV71 isolates were selected for the detection of new recombinant strains using the nucleotide sequences spanning the VP1-2A-2B region. No new recombinant strain was found. Analysis of clinical manifestations showed that patients infected with C4 had significantly higher rates of pharyngeal vesicles or ulcers than patients infected with B5. This is the first study demonstrating that different EV 71 genotypes may have different clinical manifestations and the association of EV71 infections between Taiwan and mainland China.
    Matched MeSH terms: Enterovirus Infections/complications; Enterovirus Infections/epidemiology*; Enterovirus Infections/virology
  6. Enterovirus 71 encephalomyelitis and Japanese encephalitis can be distinguished by topographic distribution of inflammation and specific intraneuronal detection of viral antigen and RNA
    Wong KT, Ng KY, Ong KC, Ng WF, Shankar SK, Mahadevan A, et al.
    Neuropathol. Appl. Neurobiol., 2012 Aug;38(5):443-53.
    PMID: 22236252 DOI: 10.1111/j.1365-2990.2011.01247.x
    To investigate if two important epidemic viral encephalitis in children, Enterovirus 71 (EV71) encephalomyelitis and Japanese encephalitis (JE) whose clinical and pathological features may be nonspecific and overlapping, could be distinguished.
    Matched MeSH terms: Enterovirus Infections/pathology*; Enterovirus Infections/virology
  7. Emerging and re-emerging epidemic encephalitis: a tale of two viruses
    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*
  8. Fulltext Validation and utilization of an internally controlled multiplex Real-time RT-PCR assay for simultaneous detection of enteroviruses and enterovirus A71 associated with hand foot and mouth disease
    Thanh TT, Anh NT, Tham NT, Van HM, Sabanathan S, Qui PT, et al.
    Virol J, 2015 Jun 09;12:85.
    PMID: 26050791 DOI: 10.1186/s12985-015-0316-2
    BACKGROUND: Hand foot and mouth disease (HFMD) is a disease of public health importance across the Asia-Pacific region. The disease is caused by enteroviruses (EVs), in particular enterovirus A71 (EV-A71). In EV-A71-associated HFMD, the infection is sometimes associated with severe manifestations including neurological involvement and fatal outcome. The availability of a robust diagnostic assay to distinguish EV-A71 from other EVs is important for patient management and outbreak response.

    METHODS: We developed and validated an internally controlled one-step single-tube real-time RT-PCR in terms of sensitivity, linearity, precision, and specificity for simultaneous detection of EVs and EV-A71. Subsequently, the assay was then applied on throat and rectal swabs sampled from 434 HFMD patients.

    RESULTS: The assay was evaluated using both plasmid DNA and viral RNA and has shown to be reproducible with a maximum assay variation of 4.41 % and sensitive with a limit of detection less than 10 copies of target template per reaction, while cross-reactivity with other EV serotypes was not observed. When compared against a published VP1 nested RT-PCR using 112 diagnostic throat and rectal swabs from 112 children with a clinical diagnosis of HFMD during 2014, the multiplex assay had a higher sensitivity and 100 % concordance with sequencing results which showed EVs in 77/112 (68.8 %) and EV-A71 in 7/112 (6.3 %). When applied to clinical diagnostics for 322 children, the assay detected EVs in throat swabs of 257/322 (79.8 %) of which EV-A71 was detected in 36/322 (11.2 %) children. The detection rate increased to 93.5 % (301/322) and 13.4 % (43/322) for EVs and EV-A71, respectively, when rectal swabs from 65 throat-negative children were further analyzed.

    CONCLUSION: We have successfully developed and validated a sensitive internally controlled multiplex assay for rapid detection of EVs and EV-A71, which is useful for clinical management and outbreak control of HFMD.

    Matched MeSH terms: Enterovirus Infections/diagnosis*
  9. Fulltext Bibliography of clinical research in Malaysia: methods and brief results
    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
  10. Fulltext Electrostatic interactions at the five-fold axis alter heparin-binding phenotype and drive enterovirus A71 virulence in mice
    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*
  11. Fulltext Enterovirus 71 can directly infect the brainstem via cranial nerves and infection can be ameliorated by passive immunization
    Tan SH, Ong KC, Wong KT
    J. Neuropathol. Exp. Neurol., 2014 Nov;73(11):999-1008.
    PMID: 25289894 DOI: 10.1097/NEN.0000000000000122
    Enterovirus 71 (EV71)-associated hand, foot, and mouth disease may be complicated by encephalomyelitis. We investigated EV71 brainstem infection and whether this infection could be ameliorated by passive immunization in a mouse model. Enterovirus 71 was injected into unilateral jaw/facial muscles of 2-week-old mice, and hyperimmune sera were given before or after infection. Harvested tissues were studied by light microscopy, immunohistochemistry, in situ hybridization, and viral titration. In unimmunized mice, viral antigen and RNA were detected within 24 hours after infection only in ipsilateral cranial nerves, motor trigeminal nucleus, reticular formation, and facial nucleus; viral titers were significantly higher in the brainstem than in the spinal cord samples. Mice given preinfection hyperimmune serum showed a marked reduction of ipsilateral viral antigen/RNA and viral titers in the brainstem in a dose-dependent manner. With optimum hyperimmune serum given after infection, brainstem infection was significantly reduced in a time-dependent manner. A delay in disease onset and a reduction of disease severity and mortality were also observed. Thus, EV71 can directly infect the brainstem, including the medulla, via cranial nerves, most likely by retrograde axonal transport. This may explain the sudden cardiorespiratory collapse in human patients with fatal encephalomyelitis. Moreover, our results suggest that passive immunization may still benefit EV71-infected patients who have neurologic complications.
    Matched MeSH terms: Enterovirus Infections/metabolism; Enterovirus Infections/prevention & control*
  12. A monoclonal antibody to ameliorate central nervous system infection and improve survival in a murine model of human Enterovirus-A71 encephalomyelitis
    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*
  13. Fulltext An enterovirus type 70 epidemic of acute conjunctivitis in peninsular Malaysia, 1980
    Tan DSK, Lee WS
    Med J Malaysia, 1981 Jun;36(2):76-8.
    PMID: 7343822
    Matched MeSH terms: Enterovirus Infections/microbiology*
  14. Entero-and myxoviral infections of the central nervous system
    Tan DS
    Med J Malaya, 1968 Dec;23(2):140-5.
    PMID: 4308419
    Matched MeSH terms: Enterovirus Infections*
  15. Fulltext Recent developments in antiviral agents against enterovirus 71 infection
    Tan CW, Lai JK, Sam IC, Chan YF
    J Biomed Sci, 2014;21:14.
    PMID: 24521134 DOI: 10.1186/1423-0127-21-14
    Enterovirus 71 (EV-71) is the main etiological agent of hand, foot and mouth disease (HFMD). Recent EV-71 outbreaks in Asia-Pacific were not limited to mild HFMD, but were associated with severe neurological complications such as aseptic meningitis and brainstem encephalitis, which may lead to cardiopulmonary failure and death. The absence of licensed therapeutics for clinical use has intensified research into anti-EV-71 development. This review highlights the potential antiviral agents targeting EV-71 attachment, entry, uncoating, translation, polyprotein processing, virus-induced formation of membranous RNA replication complexes, and RNA-dependent RNA polymerase. The strategies for antiviral development include target-based synthetic compounds, anti-rhinovirus and poliovirus libraries screening, and natural compound libraries screening. Growing knowledge of the EV-71 life cycle will lead to successful development of antivirals. The continued effort to develop antiviral agents for treatment is crucial in the absence of a vaccine. The coupling of antivirals with an effective vaccine will accelerate eradication of the disease.
    Matched MeSH terms: Enterovirus Infections/drug therapy*; Enterovirus Infections/genetics; Enterovirus Infections/pathology
  16. Fulltext Inhibition of enterovirus 71 (EV-71) infections by a novel antiviral peptide derived from EV-71 capsid protein VP1
    Tan CW, Chan YF, Sim KM, Tan EL, Poh CL
    PLoS One, 2012;7(5):e34589.
    PMID: 22563456 DOI: 10.1371/journal.pone.0034589
    Enterovirus 71 (EV-71) is the main causative agent of hand, foot and mouth disease (HFMD). In recent years, EV-71 infections were reported to cause high fatalities and severe neurological complications in Asia. Currently, no effective antiviral or vaccine is available to treat or prevent EV-71 infection. In this study, we have discovered a synthetic peptide which could be developed as a potential antiviral for inhibition of EV-71. Ninety five synthetic peptides (15-mers) overlapping the entire EV-71 capsid protein, VP1, were chemically synthesized and tested for antiviral properties against EV-71 in human Rhabdomyosarcoma (RD) cells. One peptide, SP40, was found to significantly reduce cytopathic effects of all representative EV-71 strains from genotypes A, B and C tested, with IC(50) values ranging from 6-9.3 µM in RD cells. The in vitro inhibitory effect of SP40 exhibited a dose dependent concentration corresponding to a decrease in infectious viral particles, total viral RNA and the levels of VP1 protein. The antiviral activity of SP40 peptide was not restricted to a specific cell line as inhibition of EV-71 was observed in RD, HeLa, HT-29 and Vero cells. Besides inhibition of EV-71, it also had antiviral activities against CV-A16 and poliovirus type 1 in cell culture. Mechanism of action studies suggested that the SP40 peptide was not virucidal but was able to block viral attachment to the RD cells. Substitutions of arginine and lysine residues with alanine in the SP40 peptide at positions R3A, R4A, K5A and R13A were found to significantly decrease antiviral activities, implying the importance of positively charged amino acids for the antiviral activities. The data demonstrated the potential and feasibility of SP40 as a broad spectrum antiviral agent against EV-71.
    Matched MeSH terms: Enterovirus Infections/prevention & control; Enterovirus Infections/virology
  17. VP1 residues around the five-fold axis of enterovirus A71 mediate heparan sulfate interaction
    Tan CW, Sam IC, Lee VS, Wong HV, Chan YF
    Virology, 2017 01 15;501:79-87.
    PMID: 27875780 DOI: 10.1016/j.virol.2016.11.009
    Enterovirus A71 (EV-A71) is a neurotropic enterovirus that uses heparan sulfate as an attachment receptor. The molecular determinants of EV-A71-heparan sulfate interaction are unknown. With In silico heparin docking and mutagenesis of all possible lysine residues in VP1, we identified that K162, K242 and K244 are responsible for heparin interaction and inhibition. EV-A71 mutants with K242A and K244A rapidly acquired compensatory mutations, T100K or E98A, and Q145R-T237N respectively, which restored the heparin-binding phenotype. Both VP1-98 and VP1-145 modulates heparin binding. Heparin-binding phenotype was completely abolished with VP1-E98-E145, but was restored by an E98K or E145Q substitution. During cell culture adaptation, EV-A71 rapidly acquired K98 or Q/G145 to restore the heparin-binding phenotype. Together with next-generation sequencing analysis, our results implied that EV-A71 has high genetic plasticity by modulating positively-charged residues at the five-fold axis during in vitro heparin adaptation. Our finding has impact on EV-A71 vaccine production, evolutionary studies and pathogenesis.
    Matched MeSH terms: Enterovirus Infections/metabolism*; Enterovirus Infections/virology
  18. High-titred neutralizing antibodies to human enterovirus 71 preferentially bind to the N-terminal portion of the capsid protein VP1
    Tan CS, Cardosa MJ
    Arch Virol, 2007;152(6):1069-73.
    PMID: 17318736
    Human enterovirus 71 has emerged as an important pathogen of children in the Asia Pacific region, and it may be important to consider the development of a vaccine against this virus. Human cord serum was used as a source of neutralizing antibodies to determine whether the N- or C-terminal half of the VP1 capsid protein was more likely to harbour neutralizing determinants. Cord sera from 205 individuals were tested for neutralizing antibodies against human enterovirus 71 in an indirect ELISA against recombinant VP1 antigen as well as the N- and C-terminal portions of VP1 antigen. High-titred human neutralizing antibodies were significantly more reactive with the N-terminal half of VP1 than weak or negative sera. The N-terminal half of human enterovirus 71 is likely to have important neutralizing antibody determinants and should be investigated further in vaccine development efforts.
    Matched MeSH terms: Enterovirus Infections/immunology; Enterovirus Infections/virology
  19. Complete sequence analyses of enterovirus 71 strains from fatal and non-fatal cases of the hand, foot and mouth disease outbreak in Singapore (2000)
    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
  20. Fulltext Isolation and molecular characterization of coxsackievirus A6 and coxsackievirus A16 from a case of recurrent Hand, Foot and Mouth Disease in Mumbai, Maharashtra, India, 2018
    Saxena VK, Pawar SD, Qureshi THIH, Surve P, Yadav P, Nabi F, et al.
    Virusdisease, 2020 Mar;31(1):56-60.
    PMID: 32206699 DOI: 10.1007/s13337-020-00567-1
    Hand, Foot and Mouth Disease (HFMD) is caused by multiple Enterovirus (EV) serotypes mainly coxsackievirus A6 (CV-A6), coxsackievirus A16 (CV-A16) and Enterovirus 71 (EV-A71). Recurrent HFMD infections are rarely reported. An unusual rise in HFMD cases was reported in Mumbai during May-June 2018. Stool and throat swab specimens were referred from seven children from two hospitals for laboratory diagnosis. The age group of cases ranged from 9 months to 5 years with median age 13 months. Out of seven cases, three were males and four females. One 13-month-old female case was reported twice within 21 days. Stool, throat swab specimens were tested by pan enterovirus RT-PCR and also by virus isolation using human rhabdomyosarcoma cell line for detection of Enteroviruses. Out of seven HFMD cases, CV-A6 and CV-A16 viruses were isolated from five and two cases respectively. The phylogenetic analysis of CV-A6 viruses showed their similarity with CV-A6 viruses from Finland and China, whereas the two CV-A16 isolates showed similarity with those from Japan, France, China, Sarawak and Thailand. For the recurrent HFMD case, CV-A6 and CV-A16 were isolated from the stool specimens collected during the first and second episodes, respectively. There are no reports of isolation and molecular characterization of CV-A6 and CV-A16 viruses from recurrent HFMD cases. The present study reports molecular characterization of two Enterovirus serotypes CV-A6 and CV-A16 from a recurrent HFMD case, highlighting need of virological and molecular surveillance of HFMD.
    Matched MeSH terms: Enterovirus Infections
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