Publications (58)247.47 Total impact
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Article: Multiple Independent Emergences of Type 2 Vaccine-Derived Polioviruses during a Large Outbreak in northern Nigeria.
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ABSTRACT: Since 2005, a large poliomyelitis outbreak associated with type 2 circulating vaccine-derived poliovirus (cVDPV2) has occurred in northern Nigeria, where immunization coverage with trivalent oral poliovirus vaccine (tOPV) has been low. Phylogenetic analysis of P1/capsid region sequences of isolates from each of the 403 cases reported in 2005-2011 resolved the outbreak into 23 independent VDPV2 emergences, at least seven of which established circulating lineage groups. Virus from one emergence (lineage group 2005-8; 361 isolates) was estimated to have circulated for over six years. The population of the major cVDPV2 lineage group expanded rapidly in early 2009, fell sharply after two tOPV rounds in mid-2009, and gradually expanded again through 2011. The two major determinants of attenuation of the Sabin 2 OPV strain (A(481) in the 5' -untranslated region [5' -UTR] and VP1-Ile(143)) had been replaced in all VDPV2 isolates; most A(481) 5' -UTR replacements occurred by recombination with other enteroviruses. cVDPV2 isolates representing different lineage groups had biological properties indistinguishable from those of wild polioviruses, including efficient growth in neuronal-derived HEK293 cells, the capacity to cause paralytic disease in both humans and PVR-Tg21 transgenic mice, loss of the temperature-sensitive phenotype, and the capacity for sustained person-to-person transmission. We estimate from the poliomyelitis case count and the paralytic case:infection ratio for type 2 wild poliovirus infections that ∼700,000 cVDPV2 infections have occurred during the outbreak. The detection of multiple concurrent cVDPV2 outbreaks in northern Nigeria highlights the risks of cVDPV emergence accompanying tOPV use at low rates of coverage in developing country settings.Journal of Virology 02/2013; · 5.40 Impact Factor -
Article: Oxysterol-binding protein (OSBP) family I is the target of minor enviroxime-like compounds.
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ABSTRACT: Enviroxime is an anti-picornavirus compound that targets host phosphatidylinositol-4 kinase III beta (PI4KB) activity for its anti-picornavirus activity. To date, several anti-poliovirus (PV) compounds that are associated with a common resistance mutation in viral protein 3A (a G5318A [3A-Ala70Thr] mutation in PV) similar to enviroxime have been identified. Most of these compounds have a direct inhibitory effect on PI4KB activity as well as enviroxime (designated as major enviroxime-like compounds). However, one of the compounds, AN-12-H5, showed no inhibitory effect on PI4KB, and was considered to belong to another group of enviroxime-like compounds (designated as minor enviroxime-like compounds). In the present study, we performed siRNA-sensitization assay targeting PI4KB related genes, and identified oxysterol-binding protein (OSBP) as a target of minor enviroxime-like compounds. Knockdown of OSBP and OSBP2 increased the sensitivity of the cells against PV to AN-12-H5 and a newly identified minor enviroxime-like compound T-00127-HEV2, and also to T-00127-HEV1 to a minor extent. A ligand of OSBP, 25-hydroxycholesterol (25-HC), acted as a minor enviroxime-like compound. Minor enviroxime-like compounds induced relocalization of OSBP to Golgi apparatus in the cells. Treatment of the cells with major or minor enviroxime-like compounds suppressed expression of genes (HMGCS1 and SQLE) in SREBP/SCAP regulatory pathway, and diminished endogenous phosphatidylinositol 4-phosphate (PI4P) at Golgi apparatus. Our results suggested that minor enviroxime-like compounds are phenotypically identical to 25-HC, and that major and minor enviroxime-like compounds suppress production and/or accumulation of PI4P in PV-infected cells by targeting PI4KB and OSBP family I activities, respectively.Journal of Virology 01/2013; · 5.40 Impact Factor -
Article: Vertebral osteomyelitis caused by non-tuberculous mycobacteria: case reports and review.
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ABSTRACT: There are currently few reports of vertebral osteomyelitis caused by non-tuberculous mycobacteria. To date, only 38 cases, excluding human immunodeficiency virus patients, have been reported. We describe 3 patients with vertebral osteomyelitis caused by Mycobacterium avium-intracellulare complex or Mycobacterium kansasii, and review previous reports of vertebral osteomyelitis caused by non-tuberculous mycobacteria. Case 1 is a 50-year-old man who presented with lower back pain. Radiologic examination revealed L1-L5 enhancement and paravertebral abscess. The surgical specimen was positive for Mycobacterium avium-intracellulare complex. The patient was successfully treated by surgical excision and antibiotic administration. Case 2 is a 68-year-old woman who presented with upper back pain. Spine MRI revealed multiple lesions at T9-T12, L2, L4, and L5. Her back pain worsened, and repeated MRI revealed extensive bone lesions. Mycobacterium kansasii was isolated from a T5 vertebral body specimen. Surgery was not performed. Case 3 is a 38-year-old woman who had been taking prednisolone for systemic lupus erythematosus. We diagnosed her condition as suppurative knee arthritis caused by M. avium-intracellulare complex. Vertebral MRI revealed T9 vertebral body enhancement and a paravertebral abscess at T8-T9. Tissue culture of a T9 specimen yielded M. avium-intracellulare complex. Her clinical condition improved following posterior thoracic spinal fusion. In conclusion, vertebral osteomyelitis caused by non-tuberculous mycobacteria should be included in the differential diagnosis, even in immunocompetent patients.Journal of Infection and Chemotherapy 01/2013; · 1.80 Impact Factor -
Article: [Intravenous azithromycin for treatment of an uncomplicated typhoid fever suspected primary treatment failure].
Kansenshogaku zasshi. The Journal of the Japanese Association for Infectious Diseases 07/2012; 86(4):427-9. -
Article: Reply to "poliovirus-neutralization test with poliovirus pseudovirus to measure neutralizing antibody in humans".
Clinical and vaccine immunology: CVI 03/2012; 19(3):459. · 2.37 Impact Factor -
Article: Valosin-containing protein (VCP/p97) is required for poliovirus replication and is involved in cellular protein secretion pathway in poliovirus infection.
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ABSTRACT: Poliovirus (PV) modifies membrane-trafficking machinery in host cells for its viral RNA replication. To date, ARF1, ACBD3, BIG1/BIG2, GBF1, RTN3, and PI4KB have been identified as host factors of enterovirus (EV), including PV, involved in membrane traffic. In this study, we performed small interfering RNA (siRNA) screening targeting membrane-trafficking genes for host factors required for PV replication. We identified valosin-containing protein (VCP/p97) as a host factor of PV replication required after viral protein synthesis, and its ATPase activity was essential for PV replication. VCP colocalized with viral proteins 2BC/2C and 3AB/3B in PV-infected cells and showed an interaction with 2BC and 3AB but not with 2C and 3A. Knockdown of VCP did not suppress the replication of coxsackievirus B3 or Aichi virus. A VCP-knockdown-resistant PV mutant had an A4881G (a mutation of E253G in 2C) mutation, which is known as a determinant of a secretion inhibition-negative phenotype. However, knockdown of VCP did not affect the inhibition of cellular protein secretion caused by overexpression of each individual viral protein. These results suggested that VCP is a host factor required for viral RNA replication of PV among membrane-trafficking proteins and provides a novel link between cellular protein secretion and viral RNA replication.Journal of Virology 02/2012; 86(10):5541-53. · 5.40 Impact Factor -
Article: Development of a transcription-reverse transcription concerted reaction method for specific detection of human enterovirus 71 from clinical specimens.
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ABSTRACT: A transcription-reverse transcription (RT) concerted reaction (TRCR) method was developed for rapid and specific detection of EV71 from clinical specimens. This method was validated with EV71 strains from all of the known genotypes (genotypes A, B1 to B5, and C1 to C5), with detection limits of 10 to 10(3) copies, and was useful for identification of EV71 from throat swabs of patients with hand, foot, and mouth disease (HFMD).Journal of clinical microbiology 02/2012; 50(5):1764-8. · 4.16 Impact Factor -
Article: Cellular receptors for human enterovirus species a.
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ABSTRACT: Human enterovirus species A (HEV-A) is one of the four species of HEV in the genus Enterovirus in the family Picornaviridae. Among HEV-A, coxsackievirus A16 (CVA16) and enterovirus 71 (EV71) are the major causative agents of hand, foot, and mouth disease (HFMD). Some other types of HEV-A are commonly associated with herpangina. Although HFMD and herpangina due to HEV-A are common febrile diseases among infants and children, EV71 can cause various neurological diseases, such as aseptic meningitis and fatal encephalitis. Recently, two human transmembrane proteins, P-selectin glycoprotein ligand-1 (PSGL-1) and scavenger receptor class B, member 2 (SCARB2), were identified as functional receptors for EV71 and CVA16. In in vitro infection experiments using the prototype HEV-A strains, PSGL-1 and SCARB2 could be responsible for the specific receptors for EV71 and CVA16. However, the involvement of both receptors in the in vitro and in vivo infections of clinical isolates of HEV-A has not been clarified yet. To elucidate a diverse array of the clinical outcome of HEV-A-associated diseases, the identification and characterization of HEV-A receptors may provide useful information in understanding the HEV-A pathogenesis at a molecular level.Frontiers in microbiology. 01/2012; 3:105. -
Article: Development of a poliovirus neutralization test with poliovirus pseudovirus for measurement of neutralizing antibody titer in human serum.
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ABSTRACT: In the Global Polio Eradication Initiative, laboratory diagnosis plays a critical role by isolating and identifying poliovirus (PV) from the stool samples from acute flaccid paralysis (AFP) cases. In recent years, reestablishment of PV circulation in countries where PV was previously eliminated has occurred because of decreased herd immunity, possibly due to poor vaccination coverage. To monitor the vulnerability of countries to PV circulation, surveillance of neutralizing-antibody titers against PV in susceptible populations is essential in the end game of the polio eradication program. In this study, we have developed a PV neutralization test with type 1, 2, and 3 PV pseudoviruses to determine the neutralizing-antibody titer against PV in human serum samples. With this test, the neutralizing-antibody titer against PV could be determined within 2 days by automated interpretation of luciferase signals without using infectious PV strains. We validated the pseudovirus PV neutralization test with 131 human serum samples collected from a wide range of age groups (ages 1 to >60 years) by comparison with a conventional neutralization test. We found good correlation in the neutralizing-antibody titers determined by these tests. These results suggest that a pseudovirus PV neutralization test would serve as a safe and simple procedure for the measurement of the neutralizing-antibody titer against PV.Clinical and vaccine immunology: CVI 08/2011; 18(11):1889-94. · 2.37 Impact Factor -
Article: Phosphatidylinositol 4-kinase III beta is a target of enviroxime-like compounds for antipoliovirus activity.
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ABSTRACT: Enviroxime is an antienterovirus compound that targets viral protein 3A and/or 3AB and suppresses a step in enterovirus replication by unknown mechanism. To date, four antienterovirus compounds, i.e., GW5074, Flt3 inhibitor II, TTP-8307, and AN-12-H5, are known to have similar mutations in the 3A protein-encoding region causing resistance to enviroxime (a G5318A [3A-Ala70Thr] mutation in poliovirus [PV]) and are considered enviroxime-like compounds. Recently, antienterovirus activity of a phosphatidylinositol 4-kinase III beta (PI4KB) inhibitor, PIK93, was reported, suggesting that PI4KB is an important host factor targetable by antienterovirus compounds (N. Y. Hsu et al., Cell 141:799-811, 2010). In this study, we analyzed the inhibitory effects of previously identified enviroxime-like compounds (GW5074 and AN-12-H5) and a newly identified antienterovirus compound, T-00127-HEV1, on phosphoinositide (PI) kinases. We found that T-00127-HEV1 inhibited PI4KB activity with a higher specificity for than other PI kinases, in contrast to GW5074, which had a broad specificity for PI kinases. In contrast, AN-12-H5 showed no inhibitory effect on PI4KB activity and only moderate inhibitory effects on PI 3-kinase activity. Small interfering RNA (siRNA) screening targeting PI kinases identified PI4KB is a target of GW5074 and T-00127-HEV1, but not of AN-12-H5, for anti-PV activity. Interestingly, T-00127-HEV1 and GW5074 did not inhibit hepatitis C virus (HCV) replication, in contrast to a strong inhibitory effect of AN-12-H5. These results suggested that PI4KB is an enterovirus-specific host factor required for the replication process and targeted by some enviroxime-like compounds (T-00127-HEV1 and GW5074) and that enviroxime-like compounds may have targets other than PI kinases for their antiviral effect.Journal of Virology 03/2011; 85(5):2364-72. · 5.40 Impact Factor -
Article: Particle agglutination method for poliovirus identification.
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ABSTRACT: In the Global Polio Eradication Initiative, laboratory diagnosis plays a critical role by isolating and identifying PV from the stool samples of acute flaccid paralysis (AFP) cases. In the World Health Organization (WHO) Global Polio Laboratory Network, PV isolation and identification are currently being performed by using cell culture system and real-time RT-PCR, respectively. In the post-eradication era of PV, simple and rapid identification procedures would be helpful for rapid confirmation of polio cases at the national laboratories. In the present study, we will show the procedure of novel PA assay developed for PV identification. This PA assay utilizes interaction of PV receptor (PVR) molecule and virion that is specific and uniform affinity to all the serotypes of PV. The procedure is simple (one step procedure in reaction plates) and rapid (results can be obtained within 2 h of reaction), and the result is visually observed (observation of agglutination of gelatin particles).Journal of Visualized Experiments 01/2011; -
Article: Endemic transmission of echovirus 30 in Toyama, Japan in 2010 is verified by environmental surveillance.
Japanese journal of infectious diseases. 01/2011; 64(2):165-7. -
Article: A bifunctional anti-enterovirus compound that inhibits replication and the early stage of enterovirus 71 infection.
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ABSTRACT: Enviroxime is an anti-enterovirus compound that targets viral protein 3A and/or 3AB and suppresses a replication step of enterovirus by an unknown mechanism. To date, a number of anti-enterovirus compounds that have little structural similarity to enviroxime but induce common resistance mutations in the 3A-encoding region have been identified. The present study identified a novel type of functionally enviroxime-like compound, AN-12-H5. This compound had no structural similarity to enviroxime or to known enviroxime-like compounds, including TTP-8307, GW5074 and Flt3 Inhibitor II. A resistance phenotype of poliovirus (PV) to these compounds was conferred by a major enviroxime-resistance mutation of PV (G5318A, 3A-Ala70Thr), but not by resistance mutations to guanidine hydrochloride and brefeldin A. AN-12-H5 had a common structure with the anti-enterovirus 71 (EV71) compound AN-23-F6. AN-12-H5 and AN-23-F6 inhibited an early stage of EV71 infection after virus binding to the cells. Mutations in capsid proteins (G3112A, VP1-Ala224Thr, and G2396A, VP3-Arg227Lys mutations) were determined as resistant mutations to AN-12-H5 and AN-23-F6 in the early stage of EV71 infection. These results suggest that AN-12-H5 is a bifunctional anti-enterovirus compound that belongs to a novel class of enviroxime-like compounds and targets both a replication step and an early stage of EV71 infection.Journal of General Virology 11/2010; 91(Pt 11):2734-44. · 3.36 Impact Factor -
Article: Adaptive mutations in the genomes of enterovirus 71 strains following infection of mouse cells expressing human P-selectin glycoprotein ligand-1.
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ABSTRACT: We recently identified human P-selectin glycoprotein ligand-1 (PSGL-1) as a functional enterovirus 71 (EV71) receptor and demonstrated PSGL-1-dependent replication for some EV71 strains in human leukocytes. Here, we report that four out of five PSGL-1-binding strains of EV71 replicated poorly in mouse L929 cells stably expressing human PSGL-1 (L-PSGL-1 cells). Therefore, we compared the replication kinetics and entire genomic sequence of five original EV71 strains and the corresponding EV71 variants (EV71-LPS), which were propagated once in L-PSGL-1 cells. Direct sequence comparison of the entire genome of the original EV71 strains and EV71-LPS variants identified several possible adaptive mutations during the course of replication in L-PSGL-1 cells, including a putative determinant of the adaptive phenotype in L-PSGL-1 cells at VP2-149. The results suggest that an adaptive mutation, along with a PSGL-1-binding phenotype, may facilitate efficient PSGL-1-dependent replication of the EV71 strains in L-PSGL-1 cells.Journal of General Virology 10/2010; 92(Pt 2):287-91. · 3.36 Impact Factor -
Article: Development of a particle agglutination method with soluble virus receptor for identification of poliovirus.
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ABSTRACT: In the Global Polio Eradication Initiative, laboratory diagnosis plays a critical role by isolating and identifying poliovirus (PV) from the stool samples of patients with acute flaccid paralysis (AFP). In this study, we developed a particle agglutination (PA) method with a soluble human PV receptor (hPVR) in the form of an immunoadhesin (PVR-IgG2a) for the simple and rapid identification of PV. Sensitized gelatin particles with PVR-IgG2a showed specific agglutination with the culture fluid of PV-infected cells within 2 h of reaction in a one-step procedure. Detection limits for type 1, 2, and 3 PV(Sabin) strains were 1.5 x 10(6) 50% cell culture infectious doses (CCID(50)), 5.3 x 10(5) CCID(50), and 9.1 x 10(5) CCID(50), respectively. Wild-type PVs and PV isolates from acute flaccid paralysis cases examined were identified correctly with this PA method, except for some samples with a mixture of different serotypes of PVs, where a minor population of PV failed to be detected. These results suggest that this PA method is useful for the simple and rapid identification of PV, although the sensitivity was not high enough to detect a minor population of PV (<1/10 of the major population) among mixed PVs.Journal of clinical microbiology 08/2010; 48(8):2698-702. · 4.16 Impact Factor -
Article: Tyrosine sulfation of the amino terminus of PSGL-1 is critical for enterovirus 71 infection.
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ABSTRACT: Enterovirus 71 (EV71) is one of the major causative agents of hand, foot, and mouth disease, a common febrile disease in children; however, EV71 has been also associated with various neurological diseases including fatal cases in large EV71 outbreaks particularly in the Asia Pacific region. Recently we identified human P-selectin glycoprotein ligand-1 (PSGL-1) as a cellular receptor for entry and replication of EV71 in leukocytes. PSGL-1 is a sialomucin expressed on the surface of leukocytes, serves as a high affinity counterreceptor for selectins, and mediates leukocyte rolling on the endothelium. The PSGL-1-P-selectin interaction requires sulfation of at least one of three clustered tyrosines and an adjacent O-glycan expressing sialyl Lewis x in an N-terminal region of PSGL-1. To elucidate the molecular basis of the PSGL-1-EV71 interaction, we generated a series of PSGL-1 mutants and identified the post-translational modifications that are critical for binding of PSGL-1 to EV71. We expressed the PSGL-1 mutants in 293T cells and the transfected cells were assayed for their abilities to bind to EV71 by flow cytometry. We found that O-glycosylation on T57, which is critical for PSGL-1-selectin interaction, is not necessary for PSGL-1 binding to EV71. On the other hand, site-directed mutagenesis at one or more potential tyrosine sulfation sites in the N-terminal region of PSGL-1 significantly impaired PSGL-1 binding to EV71. Furthermore, an inhibitor of sulfation, sodium chlorate, blocked the PSGL-1-EV71 interaction and inhibited PSGL-1-mediated viral replication of EV71 in Jurkat T cells in a dose-dependent manner. Thus, the results presented in this study reveal that tyrosine sulfation, but not O-glycosylation, in the N-terminal region of PSGL-1 may facilitate virus entry and replication of EV71 in leukocytes.PLoS Pathogens 01/2010; 6(11):e1001174. · 9.13 Impact Factor -
Article: [Identification of P-selectin glycoprotein ligand-1 as one of the cellular receptors for enterovirus 71].
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ABSTRACT: Enterovirus 71 (EV71) is a major causative agent of hand, foot and mouth disease (HFMD), a common febrile disease in young children. Although clinical manifestations of HFMD are usually mild and self-limiting, EV71 can cause large outbreaks of HFMD including severe neurological complications. We identified human P-selectin glycoprotein ligand-1 (PSGL-1; CD162) as a functional receptor for EV71 using an expression cloning method with a human T cell cDNA library by panning. PSGL-1 is a sialomucin membrane protein, expressed on leukocytes, that has a major role in early stages of inflammation by interacting with selections and chemokines. EV71 specifically binds to the N terminal region of PSGL-1 and the expression of human PSGL-1 allowed EV71 replication in nonsusceptible mouse cells, suggesting that PSGL-1 is a functional EV71 receptor. We found the presence of strain-specific EV71 replication in leukocytes. In addition, EV71 replicates in nonleukocyte cell lines in a PSGL-1-independent manner. Thus, further elucidation of the PSGL-1-dependent EV71 replication may provide valuable insights into the molecular basis of EV71 infection including HFMD and various neurological diseases.Uirusu 12/2009; 59(2):195-203. -
Article: Development of a reverse transcription-loop-mediated isothermal amplification (RT-LAMP) system for a highly sensitive detection of enterovirus in the stool samples of acute flaccid paralysis cases.
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ABSTRACT: In the global eradication program for poliomyelitis, the laboratory diagnosis plays a critical role by isolating poliovirus (PV) from the stool samples of acute flaccid paralysis (AFP) cases. In this study, we developed a reverse transcription-loop-mediated isothermal amplification (RT-LAMP) system for a rapid and highly sensitive detection of enterovirus including PV to identify stool samples positive for enterovirus including PV. A primer set was designed for RT-LAMP to detect enterovirus preferably those with PV-like 5'NTRs of the viral genome. The sensitivity of RT-LAMP system was evaluated with prototype strains of enterovirus. Detection of enterovirus from stool extracts was examined by using RT-LAMP system. We detected at least 400 copies of the viral genomes of PV(Sabin) strains within 90 min by RT-LAMP with the primer set. This RT-LAMP system showed a preference for Human enterovirus species C (HEV-C) strains including PV, but exhibited less sensitivity to the prototype strains of HEV-A and HEV-B (detection limits of 7,400 to 28,000 copies). Stool extracts, from which PV, HEV-C, or HEV-A was isolated in the cell culture system, were mostly positive by RT-LAMP method (positive rates of 15/16 (= 94%), 13/14 (= 93%), and 4/4 (= 100%), respectively). The positive rate of this RT-LAMP system for stool extracts from which HEV-B was isolated was lower than that of HEV-C (positive rate of 11/21 (= 52%)). In the stool samples, which were negative for enterovirus isolation by the cell culture system, we found that two samples were positive for RT-LAMP (positive rates of 2/38 (= 5.3%)). In these samples, enterovirus 96 was identified by sequence analysis utilizing a seminested PCR system. RT-LAMP system developed in this study showed a high sensitivity comparable to that of the cell culture system for the detection of PV, HEV-A, and HEV-C, but less sensitivity to HEV-B. This RT-LAMP system would be useful for the direct detection of enterovirus from the stool extracts.BMC Infectious Diseases 12/2009; 9:208. · 3.12 Impact Factor -
Article: Characterization of a rare natural intertypic type 2/type 3 penta-recombinant vaccine-derived poliovirus isolated from a child with acute flaccid paralysis.
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ABSTRACT: A type 2 vaccine-derived poliovirus (VDPV) (strain CHN1025), with a 1.1 % (10/903) difference from Sabin strain in the VP1 coding region, was isolated from a child with poliomyelitis caused by a poliovirus variant infection. The patient was from Shandong Province of China and developed acute flaccid paralysis in 1997. The child was infected with a rare and complicated penta-recombinant poliovirus with the uncommon genomic recombinant organization S2/S3/S1/S3/S1/S3. At least five successive rounds of recombination occurred in the VP1 capsid coding region and in the 2C, 3C (twice) and 3D(pol) non-capsid coding regions, respectively, during virus evolution. Strain CHN1025 had most of the characteristics of the type 2 vaccine strain; it had Sabin-specific epitopes, suggesting that the virus was antigenically indistinguishable from the Sabin 2 reference strain. Typical mutations in the 5'-untranslated region and VP1 associated with reversion to neurovirulence for Sabin 2 poliovirus were found, and the virus showed moderate neurovirulence in transgenic mice. A few nucleotide substitutions were located in the donor sequences, and two donor sequences contained no nucleotide substitutions, suggesting that these sequences were relatively new. The appearance of these mutations within approximately 192 days of at least five successive rounds of recombination events derived from a single ancestral infection illustrates the rapid emergence of new recombinants among VDPVs. This is the first report on the isolation of a type 2/type 3 poliovirus capsid recombinant with one of the five crossover sites located in the VP1 coding region.Journal of General Virology 10/2009; 91(Pt 2):421-9. · 3.36 Impact Factor -
Article: Human P-selectin glycoprotein ligand-1 is a functional receptor for enterovirus 71.
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ABSTRACT: Enterovirus 71 (EV71) is a major causative agent of hand, foot and mouth disease (HFMD), a common febrile disease occurring mainly in young children. Although clinical manifestations of HFMD are usually mild and self limiting, a severe EV71 outbreak can lead to a diverse array of neurological diseases. Identification of the specific cellular receptors is crucial for elucidating the mechanism of early virus-host interactions and the pathogenesis of enteroviruses. Here we identify human P-selectin glycoprotein ligand-1 (PSGL-1; CD162), a sialomucin membrane protein expressed on leukocytes that has a major role in early stages of inflammation, as a functional receptor for EV71 using an expression cloning method by panning. The N-terminal region of PSGL-1 binds specifically to EV71. Stable PSGL-1 expression allowed EV71 entry and replication, and development of cytopathic effects in nonsusceptible mouse L929 cells. Five out of eight EV71 strains bound soluble PSGL-1 and used intact PSGL-1 as the primary receptor for infection of Jurkat T cells. Three other EV71 strains did not use PSGL-1, suggesting the presence of strain-specific replication of EV71 in leukocytes. EV71 replicated in nonleukocyte cell lines in a PSGL-1-independent manner, indicating the presence of alternative receptor(s) for EV71. The identification of PSGL-1 as a receptor for EV71 sheds new light on a role for PSGL-1-positive leukocytes in cell tropism and pathogenesis during the course of HFMD and other EV71-mediated diseases.Nature medicine 07/2009; 15(7):794-7. · 27.14 Impact Factor
Top co-authors
Top Journals
Institutions
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2013
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Tokyo Medical University
- Department of Infection Control and Prevension
Tokyo, Tokyo-to, Japan
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2002–2013
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National Institute of Infectious Diseases, Tokyo
Tokyo, Tokyo-to, Japan
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2009
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Victorian Infectious Diseases Reference Laboratory
Melbourne, Victoria, Australia
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2008
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Yunnan Center for Disease Control and Prevention
Kunming, Yunnan, China
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2004
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Centers for Disease Control and Prevention
Atlanta, MI, USA
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