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Sarah J Butcher - One of the best experts on this subject based on the ideXlab platform.

  • a 2 8 angstrom resolution cryo electron microscopy structure of Human Parechovirus 3 in complex with fab from a neutralizing antibody
    Journal of Virology, 2018
    Co-Authors: Sarah J Butcher, James A. Geraets, Aušra Domanska, Justin W Flatt, Joonas Jukonen
    Abstract:

    ABSTRACT Human Parechovirus 3 (HPeV3) infection is associated with sepsis characterized by significant immune activation and subsequent tissue damage in neonates. Strategies to limit infection have been unsuccessful due to inadequate molecular diagnostic tools for early detection and the lack of a vaccine or specific antiviral therapy. Toward the latter, we present a 2.8-A-resolution structure of HPeV3 in complex with fragments from a neutralizing Human monoclonal antibody, AT12-015, using cryo-electron microscopy (cryo-EM) and image reconstruction. Modeling revealed that the epitope extends across neighboring asymmetric units with contributions from capsid proteins VP0, VP1, and VP3. Antibody decoration was found to block binding of HPeV3 to cultured cells. Additionally, at high resolution, it was possible to model a stretch of RNA inside the virion and, from this, identify the key features that drive and stabilize protein-RNA association during assembly. IMPORTANCE Human Parechovirus 3 (HPeV3) is receiving increasing attention as a prevalent cause of sepsis-like symptoms in neonates, for which, despite the severity of disease, there are no effective treatments available. Structural and molecular insights into virus neutralization are urgently needed, especially as clinical cases are on the rise. Toward this goal, we present the first structure of HPeV3 in complex with fragments from a neutralizing monoclonal antibody. At high resolution, it was possible to precisely define the epitope that, when targeted, prevents virions from binding to cells. Such an atomic-level description is useful for understanding host-pathogen interactions and viral pathogenesis mechanisms and for finding potential cures for infection and disease.

  • Genomic RNA folding mediates assembly of Human Parechovirus
    Nature Communications, 2017
    Co-Authors: Shabih Shakeel, Sarah J Butcher, Eric C. Dykeman, Simon J. White, Joseph J.b. Cockburn, Peter G. Stockley, Reidun Twarock
    Abstract:

    The mechanism underlying packaging of genomic RNA into viral particles is not well understood for Human Parechoviruses. Here the authors identify short RNA motifs in the Parechovirus genome that bind capsid proteins, providing approximately 60 specific interactions for virion assembly. Assembly of the major viral pathogens of the Picornaviridae family is poorly understood. Human Parechovirus 1 is an example of such viruses that contains 60 short regions of ordered RNA density making identical contacts with the protein shell. We show here via a combination of RNA-based systematic evolution of ligands by exponential enrichment, bioinformatics analysis and reverse genetics that these RNA segments are bound to the coat proteins in a sequence-specific manner. Disruption of either the RNA coat protein recognition motif or its contact amino acid residues is deleterious for viral assembly. The data are consistent with RNA packaging signals playing essential roles in virion assembly. Their binding sites on the coat proteins are evolutionarily conserved across the Parechovirus genus, suggesting that they represent potential broad-spectrum anti-viral targets.

  • genomic rna folding mediates assembly of Human Parechovirus
    Nature Communications, 2017
    Co-Authors: Shabih Shakeel, Sarah J Butcher, Eric C. Dykeman, Simon J. White, Joseph J.b. Cockburn, Peter G. Stockley, Ari Ora, Reidun Twarock
    Abstract:

    Assembly of the major viral pathogens of the Picornaviridae family is poorly understood. Human Parechovirus 1 is an example of such viruses that contains 60 short regions of ordered RNA density making identical contacts with the protein shell. We show here via a combination of RNA-based systematic evolution of ligands by exponential enrichment, bioinformatics analysis and reverse genetics that these RNA segments are bound to the coat proteins in a sequence-specific manner. Disruption of either the RNA coat protein recognition motif or its contact amino acid residues is deleterious for viral assembly. The data are consistent with RNA packaging signals playing essential roles in virion assembly. Their binding sites on the coat proteins are evolutionarily conserved across the Parechovirus genus, suggesting that they represent potential broad-spectrum anti-viral targets.

  • Interaction of αVβ3 and αVβ6 Integrins with Human Parechovirus 1
    Journal of virology, 2010
    Co-Authors: Jani J. T. Seitsonen, Timo Hyypiä, Petri Susi, Outi Heikkilä, Robert S. Sinkovits, Pasi Laurinmäki, Sarah J Butcher
    Abstract:

    Human Parechovirus (HPEV) infections are very common in early childhood and can be severe in neonates. It has been shown that integrins are important for cellular infectivity of HPEV1 through experiments using peptide blocking assays and function-blocking antibodies to alpha(V) integrins. The interaction of HPEV1 with alpha(V) integrins is presumably mediated by a C-terminal RGD motif in the capsid protein VP1. We characterized the binding of integrins alpha(V)beta(3) and alpha(V)beta(6) to HPEV1 by biochemical and structural studies. We showed that although HPEV1 bound efficiently to immobilized integrins, alpha(V)beta(6) bound more efficiently than alpha(V)beta(3) to immobilized HPEV1. Moreover, soluble alpha(V)beta(6), but not alpha(V)beta(3), blocked HPEV1 cellular infectivity, indicating that it is a high-affinity receptor for HPEV1. We also showed that HPEV1 binding to integrins in vitro could be partially blocked by RGD peptides. Using electron cryo-microscopy and image reconstruction, we showed that HPEV1 has the typical T=1 (pseudo T=3) organization of a picornavirus. Complexes of HPEV1 and integrins indicated that both integrin footprints reside between the 5-fold and 3-fold symmetry axes. This result does not match the RGD position predicted from the coxsackievirus A9 X-ray structure but is consistent with the predicted location of this motif in the shorter C terminus found in HPEV1. This first structural characterization of a Parechovirus indicates that the differences in receptor binding are due to the amino acid differences in the integrins rather than to significantly different viral footprints.

Akihiko Saitoh - One of the best experts on this subject based on the ideXlab platform.

  • Human Parechovirus type 3 infection an emerging infection in neonates and young infants
    Journal of Infection and Chemotherapy, 2017
    Co-Authors: Yuta Aizawa, Ryohei Izumita, Akihiko Saitoh
    Abstract:

    Human Parechoviruses (HPeVs) are RNA viruses that have characteristics similar to those of enteroviruses and usually cause mild respiratory or gastrointestinal symptoms. Human Parechovirus type 3 (HPeV3), first reported in 2004, is exceptional because it can provoke sepsis and meningoencephalitis leading to neurological sequelae, and even death, in neonates and young infants. Pediatricians and researchers are increasingly aware that HPeV3 is responsible for serious disease in neonates and young infants. Retrospective studies and several reports of epidemics of HPeV3 infection have provided data on epidemiology, clinical symptoms and signs, laboratory findings, and outcomes. However, the pathogenesis of HPeV3 infection remains unclear, which explains the lack of specific antiviral therapy and effective prevention measures. Maternal antibodies are important in protection against severe HPeV3-related disease, and this may be a clue regarding its pathogenesis. HPeV3 epidemics are likely to continue, and because the clinical manifestations of HPeV3 are severe, determining the pathogenesis of HPeV3 infection and establishing specific antiviral therapies are important goals for future research.

  • clinical utility of serum samples for Human Parechovirus type 3 infection in neonates and young infants the 2014 epidemic in japan
    Journal of Infection, 2016
    Co-Authors: Yuta Aizawa, Kanako Watanabe, Akihiko Saitoh, Tomohiro Oishi, Yuko Suzuki
    Abstract:

    During the 2014 Human Parechovirus type 3 (HPeV3) epidemic in Niigata, Japan, this prospective observational study identified HPeV3 from 43/85 (51%) febrile young infants <4 months using PCR analysis of serum (n = 42) and/or cerebrospinal fluid (CSF) (n = 32) and genetic sequencing of the VP1 region of HPeV3. HPeV3-infected patients (median age, 32 days; range, 4-113 days) were diagnosed as having sepsis (79%), sepsis-like syndrome (19%), or encephalitis with septic shock (2%). Other than fever, mottled skin (67%) was significantly more frequent in HPeV3-infected patients than other virus-infected patients (P = 0.005). The rate of HPeV3 RNA detection in CSF without pleocytosis was high (88%; 28/32). Among the 32 patients whose serum and CSF samples were available, all patients were positive for serum PCR; however, 4 (12%) patients were negative for CSF PCR. Serum HPeV3 RNA level on admission was associated with younger age (P = 0.002), bad temper (P = 0.041), and grunting (P = 0.008). Among 6 patients with sequential data on serum HPeV3 RNA level, levels decreased rapidly without specific therapy. In conclusion, serum samples at disease onset are the most useful compared to CSF in detection of HPeV RNA and serum HPeV3 RNA level on admission was associated with important clinical manifestations in HPeV3-infected patients.

  • role of maternal antibodies in infants with severe diseases related to Human Parechovirus type 3
    Emerging Infectious Diseases, 2015
    Co-Authors: Yuta Aizawa, Kanako Watanabe, Tomohiro Oishi, Harunobu Hirano, Isao Hasegawa, Akihiko Saitoh
    Abstract:

    Human Parechovirus type 3 (HPeV3) is an emerging pathogen that causes sepsis and meningoencephalitis in young infants. To test the hypothesis that maternal antibodies can protect this population, we measured neutralizing antibody titers (NATs) to HPeV3 and other genotypes (HPeV1 and HPeV6) in 175 cord blood samples in Japan. The seropositivity rate (≥1:32) for HPeV3 was 61%, similar to that for the other genotypes, but decreased significantly as maternal age increased (p<0.001). Furthermore, during the 2014 HPeV3 epidemic, prospective measurement of NATs to HPeV3 in 45 patients with severe diseases caused by HPeV3 infection showed low NATs (≤1:16) at onset and persistently high NATs (≥1:512) until age 6 months. All intravenous immunoglobulin samples tested elicited high NATs to HPeV3. Our findings indicate that maternal antibodies to HPeV3 may help protect young infants from severe diseases related to HPeV3 and that antibody supplementation may benefit these patients.

  • asymptomatic children might transmit Human Parechovirus type 3 to neonates and young infants
    Journal of Clinical Virology, 2015
    Co-Authors: Yuta Aizawa, Kanako Watanabe, Akihiko Saitoh, Tomohiro Oishi, Takayuki Yamanaka
    Abstract:

    Abstract Background Human Parechovirus type 3 (HPeV3) epidemics occur worldwide and can lead to severe disease in neonates and young infants. Little is known about the source of HPeV3 infection. Objectives To investigate the source of HPeV3 infection and the role of asymptomatic children in the families of infected children. Study design During a 2014 HPeV3 epidemic in Niigata, Japan, we analyzed (1) clinical information on sick contacts for 43 neonates and young infants with HPeV3-related disease diagnosed by PCR analysis of serum and/or cerebrospinal fluid and (2) stool samples from symptomatic and asymptomatic siblings/cousins of index patients. To confirm transmission, the P1 (VP0, VP3, and VP1) and 3D pol regions of HPeVs were sequenced and analyzed. Results Sick contact with family members was confirmed for 51% ( n  = 22) of patients. Among the 30 symptomatic family members, 67% ( n  = 20) were siblings, 20% ( n  = 6) were mothers, and 13% ( n  = 4) were other relatives. Stool samples from symptomatic and asymptomatic siblings/cousins of 4 HPeV3-infected patients yielded positive results for HPeVs on PCR analysis. Furthermore, the P1 and 3D pol nucleotide sequences of family members were 100% identical to those of the respective index cases. Conclusions Identification of genetically identical virus from HPeV3-infected patients and asymptomatic children in their families suggests that the latter are a source of infection in neonates and young infants with HPeV3-related diseases.

  • dermatologic manifestations of Human Parechovirus type 3 infection in neonates and infants
    Pediatric Infectious Disease Journal, 2012
    Co-Authors: Kensuke Shoji, Hisako Komuro, Ippei Miyata, Isao Miyairi, Akihiko Saitoh
    Abstract:

    Background Human Parechovirus type 3 (HPeV3) infection can cause sepsis-like syndrome and meningoencephalitis in neonates and young infants. Although maculopapular rash is a reported clinical manifestation of HPeV3 infection, the frequency and detailed characteristics of rash in neonates and young infants with HPeV3 infection are unknown. Methods We retrospectively reviewed the clinical characteristics of neonates and young infants who received a diagnosis of HPeV3 infection on the basis of real-time polymerase chain reaction analysis of serum and/or cerebrospinal fluid specimens at the National Center for Child Health and Development in Tokyo between November 2010 and September 2011. Results Fifteen neonates and young infants were diagnosed as having HPeV3 infection; median age was 33 days (range: 10-81 days). The most common clinical presentation on admission was fever (80%), the median duration of which was 3 days (range: 1-4 days). Five (33%) children required admission to the intensive care unit for close observation, and 2 (13%) required mechanical ventilation for cardiovascular instability. After hospitalization, all children developed rash, mainly on the extremities, at a mean of 3 days (range: 1-5 days) after fever onset. The most striking finding was that 80% (12/15) of patients developed a distinctive palmar-plantar erythematous rash, which disappeared after a median of 3 days (range: 2-7 days). All patients were discharged from hospital without serious sequelae. Conclusions Palmar-plantar erythema in febrile neonates and young infants may be a diagnostic clue of HPeV3 infection.

Soren Alexandersen - One of the best experts on this subject based on the ideXlab platform.

  • epidemic and inter epidemic burden of pediatric Human Parechovirus infection in new south wales australia 2017 2018
    Pediatric Infectious Disease Journal, 2020
    Co-Authors: Ameneh Khatami, Soren Alexandersen, Rebecca Burrell, Brendan Mcmullan, William D Rawlinson, Rodney Givney, Jen Kok, Cheryl A Jones, Kristine Macartney, Philip N Britton
    Abstract:

    BACKGROUND: Human Parechovirus (HPeV) typically infects young children, and although infection is often asymptomatic, some types (eg, HPeV3) are associated with severe clinical manifestations, including central nervous system infection or sepsis-like syndrome, particularly affecting young infants. The third documented national epidemic of HPeV occurred in Australia in 2017-2018. METHODS: Four public laboratories that perform almost all of the HPeV PCR testing in New South Wales provided data regarding HPeV tests performed from July 1, 2017 to June 30, 2018. Limited demographic and clinical data were obtained from electronic medical records for laboratory test-positive cases that presented to each of the 3 pediatric hospitals in New South Wales. RESULTS: Five hundred eighty-one HPeV-positive samples obtained from 395 cases were included in the analysis. The peak of the outbreak occurred in late November 2017 (approximately 35 new cases each week), with the main HPeV epidemic occurring between the spring and summer months of September 2017 to January 2018; although this seasonality was observed primarily in infants less than 12 months of age. Among the 388 pediatric cases, almost half were younger than 2 months (188; 47%) and only 10 were children older than 2 years. The annualized estimated incidence of laboratory confirmed HPeV infection in children was approximately 142.4 cases per 100,000 children younger than 5 years in New South Wales during the epidemic season. CONCLUSIONS: The large burden of HPeV infection and disease identified in young infants in this and previous Australian studies highlight the need for more comprehensive national surveillance of HPeV infections and improved prevention strategies.

  • evolutionary and network analysis of virus sequences from infants infected with an australian recombinant strain of Human Parechovirus type 3
    Scientific Reports, 2017
    Co-Authors: Soren Alexandersen, Tiffanie M Nelson, Jason Hodge, Julian Druce
    Abstract:

    We present the near complete virus genome sequences with phylogenetic and network analyses of potential transmission networks of a total of 18 Australian cases of Human Parechovirus type 3 (HPeV3) infection in infants in the period from 2012–2015. Overall the results support our previous finding that the Australian outbreak strain/lineage is a result of a major recombination event that took place between March 2012 and November 2013 followed by further virus evolution and possibly recombination. While the nonstructural coding region of unknown provenance appears to evolve significantly both at the nucleotide and amino acid level, the capsid encoding region derived from the Yamagata 2011 lineage of HPeV3 appears to be very stable, particularly at the amino acid level. The phylogenetic and network analyses performed support a temporal evolution from the first Australian recombinant virus sequence from November 2013 to March/April 2014, onto the 2015 outbreak. The 2015 outbreak samples fall into two separate clusters with a possible common ancestor between March/April 2014 and September 2015, with each cluster further evolving in the period from September to November/December 2015.

  • an outbreak of severe infections among australian infants caused by a novel recombinant strain of Human Parechovirus type 3
    Scientific Reports, 2017
    Co-Authors: Tiffanie M Nelson, Soren Alexandersen, Jason Hodge, Julian Druce, Peter Vuillermin, David T Williams, Rekha Jasrotia
    Abstract:

    Human Parechovirus types 1–16 (HPeV1–16) are positive strand RNA viruses in the family Picornaviridae. We investigated a 2015 outbreak of HPeV3 causing illness in infants in Victoria, Australia. Virus genome was extracted from clinical material and isolates and sequenced using a combination of next generation and Sanger sequencing. The HPeV3 outbreak genome was 98.7% similar to the HPeV3 Yamagata 2011 lineage for the region encoding the structural proteins up to nucleotide position 3115, but downstream of that the genome varied from known HPeV sequences with a similarity of 85% or less. Analysis indicated that recombination had occurred, may have involved multiple types of HPeV and that the recombination event/s occurred between March 2012 and November 2013. However the origin of the genome downstream of the recombination site is unknown. Overall, the capsid of this virus is highly conserved, but recombination provided a different non-structural protein coding region that may convey an evolutionary advantage. The indication that the capsid encoding region is highly conserved at the amino acid level may be helpful in directing energy towards the development of a preventive vaccine for expecting mothers or antibody treatment of young infants with severe disease.

Charlie C. Obihara - One of the best experts on this subject based on the ideXlab platform.

  • Human Parechovirus meningitis and gross-motor neurodevelopment in young children
    European Journal of Pediatrics, 2019
    Co-Authors: Ted M. T. Hinsbergh, Stephanie C. M. Crom, Robert Lindeboom, Marceline A. M. Furth, Charlie C. Obihara
    Abstract:

    This multicenter prospective cohort study describes the impact of Human Parechovirus meningitis on gross-motor neurodevelopment of young children. Gross-motor function was measured using Alberta Infant Motor Scale. Of a total of 38 eligible children

  • longitudinal association between Human Parechovirus central nervous system infection and gross motor neurodevelopment in young children
    Pediatric Infectious Disease Journal, 2019
    Co-Authors: Ted M T Van Hinsbergh, Roy G Elbers, Marceline Van Furth, Charlie C. Obihara
    Abstract:

    Background: A paucity of studies investigated the association between Human Parechovirus (HPeV) central nervous system (CNS) infection and motor and neurocognitive development of children. This study describes the gross-motor function (GMF) in young children during 24 months after HPeV-CNS infection compared with children in whom no pathogen was detected. Methods: GMF of children was assessed with Alberta Infant Motor Scale, Bayley Scales of Infant and Toddler Development or Movement Assessment Battery for Children. We conducted multivariate analyses and adjusted for age at onset, maternal education and time from infection. Results: Of 91 included children, at onset <24 months of age, 11 had HPeV-CNS infection and in 47 no pathogen was detected. Nineteen children were excluded because of the presence of other infection, preterm birth or genetic disorder, and in 14 children, parents refused to consent for participation. We found no longitudinal association between HPeV-CNS infection and GMF (β = -0.53; 95% confidence interval: -1.18 to 0.07; P = 0.11). At 6 months, children with HPeV-CNS infection had suspect GMF delay compared with the nonpathogen group (mean difference = 1.12; 95% confidence interval: -1.96 to -0.30; P = 0.03). This difference disappeared during 24-month follow-up and, after adjustment for age at onset, both groups scored within the normal range for age. Maternal education and time from infection did not have any meaningful influence. Conclusions: We found no longitudinal association between HPeV-CNS infection and GMF during the first 24-month follow-up. Children with HPeV-CNS infection showed a suspect GMF delay at 6-month follow-up. This normalized during 24-month follow-up.

Sindy Böttcher - One of the best experts on this subject based on the ideXlab platform.

  • detection and characterization of Human enteroviruses Human cosaviruses and a new Human Parechovirus type in healthy individuals in osun state nigeria 2016 2017
    Viruses, 2019
    Co-Authors: Folakemi Abiodun Osundare, Sabine Diedrich, Oladele Oluyinka Opaleye, Akeem A Akindele, Samuel A Adedokun, Olusola Anuoluwapo Akanbi, Clausthomas Bock, Sindy Böttcher
    Abstract:

    Human enteroviruses and Human Parechoviruses are associated with a broad range of diseases and even severe and fatal conditions. For Human cosaviruses, the etiological role is yet unknown. Little is known about the circulation of non-polio enteroviruses, Human Parechoviruses, and Human cosaviruses in Nigeria. A total of 113 stool samples were collected from healthy individuals in Osun State between February 2016 and May 2017. RT-PCR assays targeting the 5' non-coding region (5' -NCR) were used to screen for Human enteroviruses, Human Parechoviruses, and Human cosaviruses. For Human enteroviruses, species-specific RT-PCR assays targeting the VP1 regions were used for molecular typing. Inoculation was carried out on RD-A, CaCo-2, HEp-2C, and L20B cell lines to compare molecular and virological assays. Ten samples tested positive for enterovirus RNA with 11 strains detected, including CV-A13 (n = 3), E-18 (n = 2), CV-A20 (n = 1), CV-A24 (n = 1), EV-C99 (n = 1), and EV-C116 (n = 2). Three samples tested positive for Human Parechovirus RNA, and full genome sequencing on two samples allowed assignment to a new Parechovirus A type (HPeV-19). Thirty-three samples tested positive for cosavirus with assignment to species Cosavirus D and Cosavirus A based on the 5'-NCR region. Screening of stool samples collected from healthy individuals in Nigeria in 2016 and 2017 revealed a high diversity of circulating Human enteroviruses, Human Parechoviruses, and Human cosaviruses. Molecular assays for genotyping showed substantial benefits compared with those of cell-culture assays.

  • high diversity of Human Parechovirus including novel types in stool samples from ghanaian children
    Journal of Clinical Virology, 2017
    Co-Authors: Silke Graul, Sindy Böttcher, Daniel Eibach, Ralf Krumkamp, Julia Kasmaier, Yaw Adusarkodie, Jurgen May, Egbert Tannich, Marcus Panning
    Abstract:

    Abstract Background Little is known on Human Parechovirus (HPeV) infections in Africa. Objectives We aimed to determine the prevalence, genetic diversity, and association with diarrhea of HPeV in Ghanaian children. Study design A total of 682 stool samples from a pediatric case-control study on causes of diarrhea collected in 2007–2008 were used. Laboratory analysis included HPeV real-time RT-PCR and sequencing partial viral protein (VP) 1 gene region of HPeV. In addition, data on co-infections using the xTAG Gastrointestinal Pathogen Panel were available. Results Overall, a prevalence of 24% was found and 14 different HPeV types were detected. Phylogenetic analysis of the VP1 region indicated a novel type tentatively designated as HPeV-18. No association with diarrhea was found (OR = 0.8; 95% CI: 0.5–1.1), and HPeV viral concentrations were not different among cases and controls. No seasonal pattern was observed. HPeV-positive cases displayed a slightly higher chance of co-infections. Conclusions A high prevalence and genetic diversity of HPeV including novel types was found by sequencing partial VP 1 region. HPeV was not associated with diarrheal disease in this pediatric population and the high number of co-infection suggests transient colonization without clinical relevance.

  • Human Parechovirus Infections Associated with Seizures and Rash in Infants and Toddlers.
    The Pediatric infectious disease journal, 2015
    Co-Authors: Katharina Karsch, Patrick Obermeier, Christian Hoppe, Lea Seeber, Susann Mühlhans, Xi Chen, Franziska Tief, Tim Conrad, Sindy Böttcher, Sabine Diedrich
    Abstract:

    Background:Systematic investigations assessing the clinical impact of Human Parechovirus (HPeV) disease are sparse. Noninvasive stool samples may be useful for targeted hospital-based surveillance.Methods:In the context of a quality management program, all hospitalized children fulfilling predefined