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Merja Roivainen - One of the best experts on this subject based on the ideXlab platform.

  • Cellular Tropism of Human Enterovirus D Species Serotypes EV-94, EV-70, and EV-68 In Vitro: Implications for Pathogenesis
    Journal of medical virology, 2010
    Co-Authors: Teemu Smura, Svetlana Kaijalainen, Petri Ylipaasto, Paivi Klemola, L Kyllonen, Valeria Sordi, Lorenzo Piemonti, Merja Roivainen
    Abstract:

    Enterovirus 94 (EV-94) is an Enterovirus serotype described recently which, together with EV-68 and EV-70, forms Human Enterovirus D species. This study investigates the seroprevalences of these three serotypes and their abilities to infect, replicate, and damage cell types considered to be essential for Enterovirus-induced diseases. The cell types studied included Human leukocyte cell lines, primary endothelial cells, and pancreatic islets. High prevalence of neutralizing antibodies against EV-68 and EV-94 was found in the Finnish population. The virus strains studied had wide leukocyte tropism. EV-94 and EV-68 were able to produce infectious progeny in leukocyte cell lines with monocytic, granulocytic, T-cell, or B-cell characteristics. EV-94 and EV-70 were capable of infecting primary Human umbilical vein endothelial cells, whereas EV-68 had only marginal progeny production and did not induce cytopathic effects in these cells. Intriguingly, EV-94 was able to damage pancreatic islet β-cells, to infect, replicate, and cause necrosis in Human pancreatic islets, and to induce proinflammatory and chemoattractive cytokine expression in endothelial cells. These results suggest that HEV-D viruses may be more prevalent than has been thought previously, and they provide in vitro evidence that EV-94 may be a potent pathogen and should be considered a potentially diabetogenic Enterovirus type.

  • cellular tropism of Human Enterovirus d species serotypes ev 94 ev 70 and ev 68 in vitro implications for pathogenesis
    Journal of Medical Virology, 2010
    Co-Authors: Teemu Smura, Svetlana Kaijalainen, Petri Ylipaasto, Paivi Klemola, L Kyllonen, Valeria Sordi, Lorenzo Piemonti, Merja Roivainen
    Abstract:

    Enterovirus 94 (EV-94) is an Enterovirus serotype described recently which, together with EV-68 and EV-70, forms Human Enterovirus D species. This study investigates the seroprevalences of these three serotypes and their abilities to infect, replicate, and damage cell types considered to be essential for Enterovirus-induced diseases. The cell types studied included Human leukocyte cell lines, primary endothelial cells, and pancreatic islets. High prevalence of neutralizing antibodies against EV-68 and EV-94 was found in the Finnish population. The virus strains studied had wide leukocyte tropism. EV-94 and EV-68 were able to produce infectious progeny in leukocyte cell lines with monocytic, granulocytic, T-cell, or B-cell characteristics. EV-94 and EV-70 were capable of infecting primary Human umbilical vein endothelial cells, whereas EV-68 had only marginal progeny production and did not induce cytopathic effects in these cells. Intriguingly, EV-94 was able to damage pancreatic islet β-cells, to infect, replicate, and cause necrosis in Human pancreatic islets, and to induce proinflammatory and chemoattractive cytokine expression in endothelial cells. These results suggest that HEV-D viruses may be more prevalent than has been thought previously, and they provide in vitro evidence that EV-94 may be a potent pathogen and should be considered a potentially diabetogenic Enterovirus type. J. Med. Virol. 82:1940–1949, 2010. © 2010 Wiley-Liss, Inc.

  • Enterovirus 94, a proposed new serotype in Human Enterovirus species D.
    Journal of General Virology, 2007
    Co-Authors: Teemu Smura, Soile Blomqvist, Tapani Hovi, Lars O. Magnius, Anja Paananen, Nina Junttila, Helene Norder, Svetlana Kaijalainen, Merja Roivainen
    Abstract:

    The genus Enterovirus (family Picornaviridae) contains five species with strains isolated from Humans: Human Enterovirus A (HEV-A), HEV-B, HEV-C, HEV-D and Poliovirus. In this study, a proposed new serotype of HEV-D was characterized. Four virus strains were isolated from sewage in Egypt and one strain from acute flaccid paralysis cases in the Democratic Republic of the Congo. The complete genome of one environmental isolate, the complete coding sequence of one clinical isolate and complete VP1 regions from the other isolates were sequenced. These isolates had 66.6–69.4 % nucleotide similarity and 74.7–76.6 % amino acid sequence similarity in the VP1 region with the closest Enterovirus serotype, Enterovirus 70 (EV70), suggesting that the isolates form a new Enterovirus type, tentatively designated Enterovirus 94 (EV94). Phylogenetic analyses including sequences of the 5′ UTR, VP1 and 3D regions demonstrated that EV94 isolates formed a monophyletic group within the species HEV-D. No evidence of recombination was found between EV94 and the other HEV-D serotypes, EV68 and EV70. Further biological characterization showed that EV94 was acid stable and had a wide cell tropism in vitro. Attempts to prevent replication with protective antibodies to known Enterovirus receptors (poliovirus receptor, vitronectin α v β 3 receptor and decay accelerating factor) were not successful. Seroprevalence studies in the Finnish population revealed a high prevalence of this virus over the past two decades.

Teemu Smura - One of the best experts on this subject based on the ideXlab platform.

  • Cellular Tropism of Human Enterovirus D Species Serotypes EV-94, EV-70, and EV-68 In Vitro: Implications for Pathogenesis
    Journal of medical virology, 2010
    Co-Authors: Teemu Smura, Svetlana Kaijalainen, Petri Ylipaasto, Paivi Klemola, L Kyllonen, Valeria Sordi, Lorenzo Piemonti, Merja Roivainen
    Abstract:

    Enterovirus 94 (EV-94) is an Enterovirus serotype described recently which, together with EV-68 and EV-70, forms Human Enterovirus D species. This study investigates the seroprevalences of these three serotypes and their abilities to infect, replicate, and damage cell types considered to be essential for Enterovirus-induced diseases. The cell types studied included Human leukocyte cell lines, primary endothelial cells, and pancreatic islets. High prevalence of neutralizing antibodies against EV-68 and EV-94 was found in the Finnish population. The virus strains studied had wide leukocyte tropism. EV-94 and EV-68 were able to produce infectious progeny in leukocyte cell lines with monocytic, granulocytic, T-cell, or B-cell characteristics. EV-94 and EV-70 were capable of infecting primary Human umbilical vein endothelial cells, whereas EV-68 had only marginal progeny production and did not induce cytopathic effects in these cells. Intriguingly, EV-94 was able to damage pancreatic islet β-cells, to infect, replicate, and cause necrosis in Human pancreatic islets, and to induce proinflammatory and chemoattractive cytokine expression in endothelial cells. These results suggest that HEV-D viruses may be more prevalent than has been thought previously, and they provide in vitro evidence that EV-94 may be a potent pathogen and should be considered a potentially diabetogenic Enterovirus type.

  • cellular tropism of Human Enterovirus d species serotypes ev 94 ev 70 and ev 68 in vitro implications for pathogenesis
    Journal of Medical Virology, 2010
    Co-Authors: Teemu Smura, Svetlana Kaijalainen, Petri Ylipaasto, Paivi Klemola, L Kyllonen, Valeria Sordi, Lorenzo Piemonti, Merja Roivainen
    Abstract:

    Enterovirus 94 (EV-94) is an Enterovirus serotype described recently which, together with EV-68 and EV-70, forms Human Enterovirus D species. This study investigates the seroprevalences of these three serotypes and their abilities to infect, replicate, and damage cell types considered to be essential for Enterovirus-induced diseases. The cell types studied included Human leukocyte cell lines, primary endothelial cells, and pancreatic islets. High prevalence of neutralizing antibodies against EV-68 and EV-94 was found in the Finnish population. The virus strains studied had wide leukocyte tropism. EV-94 and EV-68 were able to produce infectious progeny in leukocyte cell lines with monocytic, granulocytic, T-cell, or B-cell characteristics. EV-94 and EV-70 were capable of infecting primary Human umbilical vein endothelial cells, whereas EV-68 had only marginal progeny production and did not induce cytopathic effects in these cells. Intriguingly, EV-94 was able to damage pancreatic islet β-cells, to infect, replicate, and cause necrosis in Human pancreatic islets, and to induce proinflammatory and chemoattractive cytokine expression in endothelial cells. These results suggest that HEV-D viruses may be more prevalent than has been thought previously, and they provide in vitro evidence that EV-94 may be a potent pathogen and should be considered a potentially diabetogenic Enterovirus type. J. Med. Virol. 82:1940–1949, 2010. © 2010 Wiley-Liss, Inc.

  • Enterovirus 94, a proposed new serotype in Human Enterovirus species D.
    Journal of General Virology, 2007
    Co-Authors: Teemu Smura, Soile Blomqvist, Tapani Hovi, Lars O. Magnius, Anja Paananen, Nina Junttila, Helene Norder, Svetlana Kaijalainen, Merja Roivainen
    Abstract:

    The genus Enterovirus (family Picornaviridae) contains five species with strains isolated from Humans: Human Enterovirus A (HEV-A), HEV-B, HEV-C, HEV-D and Poliovirus. In this study, a proposed new serotype of HEV-D was characterized. Four virus strains were isolated from sewage in Egypt and one strain from acute flaccid paralysis cases in the Democratic Republic of the Congo. The complete genome of one environmental isolate, the complete coding sequence of one clinical isolate and complete VP1 regions from the other isolates were sequenced. These isolates had 66.6–69.4 % nucleotide similarity and 74.7–76.6 % amino acid sequence similarity in the VP1 region with the closest Enterovirus serotype, Enterovirus 70 (EV70), suggesting that the isolates form a new Enterovirus type, tentatively designated Enterovirus 94 (EV94). Phylogenetic analyses including sequences of the 5′ UTR, VP1 and 3D regions demonstrated that EV94 isolates formed a monophyletic group within the species HEV-D. No evidence of recombination was found between EV94 and the other HEV-D serotypes, EV68 and EV70. Further biological characterization showed that EV94 was acid stable and had a wide cell tropism in vitro. Attempts to prevent replication with protective antibodies to known Enterovirus receptors (poliovirus receptor, vitronectin α v β 3 receptor and decay accelerating factor) were not successful. Seroprevalence studies in the Finnish population revealed a high prevalence of this virus over the past two decades.

Peter C Mcminn - One of the best experts on this subject based on the ideXlab platform.

  • Ribavirin-Resistant Mutants of Human Enterovirus 71 Express a High Replication Fidelity Phenotype during Growth in Cell Culture
    2016
    Co-Authors: Sara Sadeghipour, Emily J. Bek, Peter C Mcminn
    Abstract:

    It has been shown in animal models that ribavirin-resistant poliovirus with a G64Smutation in its 3D polymerase has high repli-cation fidelity coupled with attenuated virulence. Here, we describe the effects of mutagenesis in the Human Enterovirus 71 (HEV71) 3D polymerase on ribavirin resistance and replication fidelity. Seven substitutions were introduced at amino acid posi-tion 3D-G64 of a HEV71 full-length infectious cDNA clone (26M). Viable clone-derived virus populations were rescued from the G64N, G64R, and G64Tmutant cDNA clones. The clone-derived G64R and G64Tmutant virus populations were resistant to growth inhibition in the presence of 1,600M ribavirin, whereas the growth of parental 26M and the G64Nmutant viruses were inhibited in the presence of 800M ribavirin. Nucleotide sequencing of the 2C and 3D coding regions revealed that the rate of randommutagenesis after 13 passages in the presence of 400M ribavirin was nearly 10 times higher in the 26M genome than in the mutant G64R virus genome. Furthermore, randommutations acquired in the 2C coding regions of 26M and G64N conferred resistance to growth inhibition in the presence of 0.5 mM guanidine, whereas the G64R and G64Tmutant virus populations re-mained susceptible to growth inhibition by 0.5 mM guanidine. Interestingly, a S264Lmutation identified in the 3D coding re-gion of 26M after ribavirin selection was also associated with both ribavirin-resistant and high replication fidelity phenotypes. These findings are consistent with the hypothesis that the 3D-G64R, 3D-G64T, and 3D-S264Lmutations confer resistance upon HEV71 to the antiviral mutagen ribavirin, coupled with a high replication fidelity phenotype during growth in cell culture. Human Enterovirus 71 (HEV71) belongs to the genus Entero-viruswithin the family Picornaviridae. HEV71 is composed o

  • ribavirin resistant mutants of Human Enterovirus 71 express a high replication fidelity phenotype during growth in cell culture
    Journal of Virology, 2013
    Co-Authors: Sara Sadeghipour, Emily J. Bek, Peter C Mcminn
    Abstract:

    It has been shown in animal models that ribavirin-resistant poliovirus with a G64S mutation in its 3D polymerase has high replication fidelity coupled with attenuated virulence. Here, we describe the effects of mutagenesis in the Human Enterovirus 71 (HEV71) 3D polymerase on ribavirin resistance and replication fidelity. Seven substitutions were introduced at amino acid position 3D-G64 of a HEV71 full-length infectious cDNA clone (26M). Viable clone-derived virus populations were rescued from the G64N, G64R, and G64T mutant cDNA clones. The clone-derived G64R and G64T mutant virus populations were resistant to growth inhibition in the presence of 1,600 μM ribavirin, whereas the growth of parental 26M and the G64N mutant viruses were inhibited in the presence of 800 μM ribavirin. Nucleotide sequencing of the 2C and 3D coding regions revealed that the rate of random mutagenesis after 13 passages in the presence of 400 μM ribavirin was nearly 10 times higher in the 26M genome than in the mutant G64R virus genome. Furthermore, random mutations acquired in the 2C coding regions of 26M and G64N conferred resistance to growth inhibition in the presence of 0.5 mM guanidine, whereas the G64R and G64T mutant virus populations remained susceptible to growth inhibition by 0.5 mM guanidine. Interestingly, a S264L mutation identified in the 3D coding region of 26M after ribavirin selection was also associated with both ribavirin-resistant and high replication fidelity phenotypes. These findings are consistent with the hypothesis that the 3D-G64R, 3D-G64T, and 3D-S264L mutations confer resistance upon HEV71 to the antiviral mutagen ribavirin, coupled with a high replication fidelity phenotype during growth in cell culture.

  • a single mutation in capsid protein vp1 q145e of a genogroup c4 strain of Human Enterovirus 71 generates a mouse virulent phenotype
    Journal of General Virology, 2012
    Co-Authors: Zainun Zaini, Peter C Mcminn
    Abstract:

    We modified the capsid protein of a Human Enterovirus 71 (HEV71) belonging to subgenogroup C4 (HEV71-C4) to generate a mouse virulent strain, based on the genetic information derived from our previous subgenogroup B3 mouse-adapted virus. Infectious clone-derived mutant virus populations containing the capsid protein mutations VP1-Q145E and VP1-Q145G were generated by site-directed mutagenesis of an infectious clone of a subgenogroup C4 strain. Viruses expressing the VP1-Q145E were virulent in 5-day-old BALB/c mice with 100 % mortality rate observed. Skeletal muscle appears to be the primary site of replication of this virus with limb muscle showing severe myositis. Virus was also isolated from spleen, liver, heart and brain of infected mice. This study demonstrates that introducing a key mutation into the HEV71 VP1 capsid protein is able to generate a mouse virulent HEV71 strain from a different genogroup as well as providing an alternative strategy for the generation of mouse virulent HEV71.

  • mouse adaptation of a sub genogroup b5 strain of Human Enterovirus 71 is associated with a novel lysine to glutamic acid substitution at position 244 in protein vp1
    Virus Research, 2012
    Co-Authors: Zainun Zaini, Patchara Phuektes, Peter C Mcminn
    Abstract:

    Most Human Enterovirus 71 (HEV71) strains infect only primates and are unable to cause clinically apparent infection in mice. Here we describe a mouse-adapted HEV71 strain that belongs to sub-genogroup B5 with increased virulence in newborn BALB/c mice. The mouse-virulent strain was initially selected by serial passage of a HEV71 clinical isolate (HEV71-B5) in Chinese hamster ovary (CHO) cells (CHO-B5), followed by serial passage in newborn mice. Virus from the fifth mouse passage was cultured twice on Vero cells and designated as MP-B5. MP-B5 induces severe disease of high mortality in newborn mice in a dose-dependent manner. Skeletal muscle is the primary site of virus replication and results in severe myositis. CHO-B5 harbours a single amino acid substitution (K(149) → I) in the VP2 capsid protein. Five additional nucleotide sequence changes were identified in MP-B5, two of which are located in the 5' UTR and the three within the open reading frame (ORF). Two of the ORF mutations resulted in deduced amino acid changes in the capsid protein VP1: S(241) → L and K(244) → E; the third ORF mutation was a synonymous C → T change at nucleotide position 6072 within the 3D polymerase gene. Infectious cDNA clone-derived mutant virus populations of HEV71 belonging to sub-genogroup B3 (CHO-26 M) that contain the VP1 mutations identified in MP-B5 were generated in order to determine the mutation(s) responsible for mouse virulence. Only viruses expressing the VP1 (K(244) → E) mutation were virulent in 5-day-old BALB/c mice, indicating that the VP1 (K(244) → E) change is the critical genetic determinant of mouse adaptation and virulence in this model.

  • recent advances in the molecular epidemiology and control of Human Enterovirus 71 infection
    Current Opinion in Virology, 2012
    Co-Authors: Peter C Mcminn
    Abstract:

    Human Enterovirus 71 (HEV71) has emerged as an important cause of viral encephalitis in the Southeast Asia over the past 15 years. A pattern of increased epidemic activity and endemic circulation of HEV71 has been observed since 1997 and is associated with the regular emergence of new genetic lineages. Although the reason for this increase in HEV71 circulation remains unknown, evidence is accumulating that recombination events may drive the evolution of new genetic lineages. Prevention of HEV71 epidemics is likely to require the development of an effective vaccine. Fortunately, several candidate EV71 vaccines have recently been reported, several of which have been shown to be effective in animal models and commenced clinical trial in 2010. Furthermore, ongoing investigations into the molecular basis of HEV71 infection and virulence have pointed the way towards novel approaches to live attenuated vaccine development.

Svetlana Kaijalainen - One of the best experts on this subject based on the ideXlab platform.

  • Cellular Tropism of Human Enterovirus D Species Serotypes EV-94, EV-70, and EV-68 In Vitro: Implications for Pathogenesis
    Journal of medical virology, 2010
    Co-Authors: Teemu Smura, Svetlana Kaijalainen, Petri Ylipaasto, Paivi Klemola, L Kyllonen, Valeria Sordi, Lorenzo Piemonti, Merja Roivainen
    Abstract:

    Enterovirus 94 (EV-94) is an Enterovirus serotype described recently which, together with EV-68 and EV-70, forms Human Enterovirus D species. This study investigates the seroprevalences of these three serotypes and their abilities to infect, replicate, and damage cell types considered to be essential for Enterovirus-induced diseases. The cell types studied included Human leukocyte cell lines, primary endothelial cells, and pancreatic islets. High prevalence of neutralizing antibodies against EV-68 and EV-94 was found in the Finnish population. The virus strains studied had wide leukocyte tropism. EV-94 and EV-68 were able to produce infectious progeny in leukocyte cell lines with monocytic, granulocytic, T-cell, or B-cell characteristics. EV-94 and EV-70 were capable of infecting primary Human umbilical vein endothelial cells, whereas EV-68 had only marginal progeny production and did not induce cytopathic effects in these cells. Intriguingly, EV-94 was able to damage pancreatic islet β-cells, to infect, replicate, and cause necrosis in Human pancreatic islets, and to induce proinflammatory and chemoattractive cytokine expression in endothelial cells. These results suggest that HEV-D viruses may be more prevalent than has been thought previously, and they provide in vitro evidence that EV-94 may be a potent pathogen and should be considered a potentially diabetogenic Enterovirus type.

  • cellular tropism of Human Enterovirus d species serotypes ev 94 ev 70 and ev 68 in vitro implications for pathogenesis
    Journal of Medical Virology, 2010
    Co-Authors: Teemu Smura, Svetlana Kaijalainen, Petri Ylipaasto, Paivi Klemola, L Kyllonen, Valeria Sordi, Lorenzo Piemonti, Merja Roivainen
    Abstract:

    Enterovirus 94 (EV-94) is an Enterovirus serotype described recently which, together with EV-68 and EV-70, forms Human Enterovirus D species. This study investigates the seroprevalences of these three serotypes and their abilities to infect, replicate, and damage cell types considered to be essential for Enterovirus-induced diseases. The cell types studied included Human leukocyte cell lines, primary endothelial cells, and pancreatic islets. High prevalence of neutralizing antibodies against EV-68 and EV-94 was found in the Finnish population. The virus strains studied had wide leukocyte tropism. EV-94 and EV-68 were able to produce infectious progeny in leukocyte cell lines with monocytic, granulocytic, T-cell, or B-cell characteristics. EV-94 and EV-70 were capable of infecting primary Human umbilical vein endothelial cells, whereas EV-68 had only marginal progeny production and did not induce cytopathic effects in these cells. Intriguingly, EV-94 was able to damage pancreatic islet β-cells, to infect, replicate, and cause necrosis in Human pancreatic islets, and to induce proinflammatory and chemoattractive cytokine expression in endothelial cells. These results suggest that HEV-D viruses may be more prevalent than has been thought previously, and they provide in vitro evidence that EV-94 may be a potent pathogen and should be considered a potentially diabetogenic Enterovirus type. J. Med. Virol. 82:1940–1949, 2010. © 2010 Wiley-Liss, Inc.

  • Enterovirus 94, a proposed new serotype in Human Enterovirus species D.
    Journal of General Virology, 2007
    Co-Authors: Teemu Smura, Soile Blomqvist, Tapani Hovi, Lars O. Magnius, Anja Paananen, Nina Junttila, Helene Norder, Svetlana Kaijalainen, Merja Roivainen
    Abstract:

    The genus Enterovirus (family Picornaviridae) contains five species with strains isolated from Humans: Human Enterovirus A (HEV-A), HEV-B, HEV-C, HEV-D and Poliovirus. In this study, a proposed new serotype of HEV-D was characterized. Four virus strains were isolated from sewage in Egypt and one strain from acute flaccid paralysis cases in the Democratic Republic of the Congo. The complete genome of one environmental isolate, the complete coding sequence of one clinical isolate and complete VP1 regions from the other isolates were sequenced. These isolates had 66.6–69.4 % nucleotide similarity and 74.7–76.6 % amino acid sequence similarity in the VP1 region with the closest Enterovirus serotype, Enterovirus 70 (EV70), suggesting that the isolates form a new Enterovirus type, tentatively designated Enterovirus 94 (EV94). Phylogenetic analyses including sequences of the 5′ UTR, VP1 and 3D regions demonstrated that EV94 isolates formed a monophyletic group within the species HEV-D. No evidence of recombination was found between EV94 and the other HEV-D serotypes, EV68 and EV70. Further biological characterization showed that EV94 was acid stable and had a wide cell tropism in vitro. Attempts to prevent replication with protective antibodies to known Enterovirus receptors (poliovirus receptor, vitronectin α v β 3 receptor and decay accelerating factor) were not successful. Seroprevalence studies in the Finnish population revealed a high prevalence of this virus over the past two decades.

Michael G. Rossmann - One of the best experts on this subject based on the ideXlab platform.

  • sialic acid dependent cell entry of Human Enterovirus d68
    Nature Communications, 2015
    Co-Authors: Ju Sheng, Geng Meng, Hendrik Jan Thibaut, Jim Baggen, Frank J. M. Van Kuppeveld, Chuan Xiao, Michael G. Rossmann
    Abstract:

    The Human Enterovirus D68 (EV-D68) is a causative agent of childhood respiratory infections, but despite its prevalence the exact mechanism mediating its cell entry have not been fully established. Here, the authors show how EV-D68 binds to sialic acid on the cell surface to initiate infection.

  • Sialic acid-dependent cell entry of Human Enterovirus D68
    Nature communications, 2015
    Co-Authors: Yue Liu, Geng Meng, Hendrik Jan Thibaut, Jim Baggen, Ju Sheng, Chuan Xiao, Frank J. M. Van Kuppeveld, Michael G. Rossmann
    Abstract:

    Human Enterovirus D68 (EV-D68) is a causative agent of childhood respiratory diseases and has now emerged as a global public health threat. Nevertheless, knowledge of the tissue tropism and pathogenesis of EV-D68 has been hindered by a lack of studies on the receptor-mediated EV-D68 entry into host cells. Here we demonstrate that cell surface sialic acid is essential for EV-D68 to bind to and infect susceptible cells. Crystal structures of EV-D68 in complex with sialylated glycan receptor analogues show that they bind into the 'canyon' on the virus surface. The sialic acid receptor induces a cascade of conformational changes in the virus to eject a fatty-acid-like molecule that regulates the stability of the virus. Thus, virus binding to a sialic acid receptor and to immunoglobulin-like receptors used by most other Enteroviruses share a conserved mechanism for priming viral uncoating and facilitating cell entry.

  • neutralizing antibodies can initiate genome release from Human Enterovirus 71
    Proceedings of the National Academy of Sciences of the United States of America, 2014
    Co-Authors: Pavel Plevka, Rushika Perera, Jane Cardosa, Peiyin Lim, Ampa Suksatu, Richard J Kuhn, Michael G. Rossmann
    Abstract:

    Antibodies were prepared by immunizing mice with empty, immature particles of Human Enterovirus 71 (EV71), a picornavirus that causes severe neurological disease in young children. The capsid structure of these empty particles is different from that of the mature virus and is similar to “A” particles encountered when picornaviruses recognize a potential host cell before genome release. The monoclonal antibody E18, generated by this immunization, induced a conformational change when incubated at temperatures between 4 °C and 37 °C with mature virus, transforming infectious virions into A particles. The resultant loss of genome that was observed by cryo-EM and a fluorescent SYBR Green dye assay inactivated the virus, establishing the mechanism by which the virus is inactivated and demonstrating that the E18 antibody has potential as an anti-EV71 therapy. The antibody-mediated virus neutralization by the induction of genome release has not been previously demonstrated. Furthermore, the present results indicate that antibodies with genome-release activity could also be produced for other picornaviruses by immunization with immature particles.

  • structure of Human Enterovirus 71 in complex with a capsid binding inhibitor
    Proceedings of the National Academy of Sciences of the United States of America, 2013
    Co-Authors: Pavel Plevka, Rushika Perera, Moh Lan Yap, Jane Cardosa, Richard Kuhn, Michael G. Rossmann
    Abstract:

    Human Enterovirus 71 is a picornavirus causing hand, foot, and mouth disease that may progress to fatal encephalitis in infants and small children. As of now, no cure is available for Enterovirus 71 infections. Small molecule inhibitors binding into a hydrophobic pocket within capsid viral protein 1 were previously shown to effectively limit infectivity of many picornaviruses. Here we report a 3.2-A-resolution X-ray structure of the Enterovirus 71 virion complexed with the capsid-binding inhibitor WIN 51711. The inhibitor replaced the natural pocket factor within the viral protein 1 pocket without inducing any detectable rearrangements in the structure of the capsid. Furthermore, we show that the compound stabilizes Enterovirus 71 virions and limits its infectivity, probably through restricting dynamics of the capsid necessary for genome release. Thus, our results provide a structural basis for development of antiEnterovirus 71 capsid-binding drugs.