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      Sialylated glycans as receptor and inhibitor of enterovirus 71 infection to DLD-1 intestinal cells

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      Virology Journal
      BioMed Central

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          Abstract

          Background

          Many viruses recognize specific sugar residues, particularly sulfated or sialylated glycans, as the infection receptors. A change of sialic acid (2-6)-linked galactose (SA-α2,6Gal) to SA-α2,3Gal determines the receptor for avian flu infection. The receptor for enterovirus 71 (EV71) infection that frequently causes fatal encephalitis in Asian children remains unclear. Currently, there is no effective vaccine or anti-virus agent for EV71 infection. Using DLD-1 intestinal cells, this study investigated whether SA-linked glycan on DLD-1 intestinal cells was a receptor for EV71, and whether natural SA-linked sugars from human milk could block EV71 infection.

          Results

          EV71 specifically infected DLD-1 intestinal cells but not K562 myeloid cells. Depletion of O-linked glycans or glycolipids, but not N-linked glycans, significantly decreased EV71 infection of DLD-1 cells. Pretreatment of DLD-1 cells with sialidase (10 mU, 2 hours) significantly reduced 20-fold EV71 replication (p < 0.01). Taken together, these results suggest that SA-linked O-glycans and glycolipids, but not N-glycans, on DLD-1 cells were responsible for EV71 infection. Purified SA-α2,3Gal and SA-α2,6Gal from human milk significantly inhibited EV71 infection of DLD-1 cells, indicating terminal SA-linked glycans could be receptors and inhibitors of EV71 infection.

          Conclusion

          This is the first in the literature to demonstrate that EV71 uses SA-linked glycans as receptors for infection, and natural SA-linked glycans from human milk can protect intestinal cells from EV71 infection. Further studies will test how a SA-containing glycan can prevent EV71 in the future.

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          Most cited references14

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          Human P-selectin glycoprotein ligand-1 is a functional receptor for enterovirus 71.

          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.
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            Epidemiology and control of hand, foot and mouth disease in Singapore, 2001-2007.

            We reviewed the epidemiology of hand, foot and mouth disease (HFMD) in Singapore after the 2000 epidemic caused by Enterovirus 71 (EV71), with particular reference to the cyclical pattern, predominant circulating enteroviruses and impact of prevention and control measures in preschool centres. We analysed the epidemiological data from all clinical cases and deaths of HFMD diagnosed by medical practitioners and notified to the Ministry of Health, as well as laboratory data on enteroviruses detected among HFMD patients maintained by the Department of Pathology, Singapore General Hospital, and the Microbiology Laboratory, KK Women's and Children's Hospital from 2001 to 2007. The incidence rate was highest in the 0 to 4 years old age group, with males being predominant. Three deaths were reported between January and February 2001. Nationwide epidemics occurred periodically; the predominating circulating virus was Coxsackievirus A16 (CA16) in the 2002, 2005 and 2007 epidemics, and EV71 in the 2006 epidemic. During the epidemic years between 2005 and 2007, 2 peaks were observed. The number of institutional outbreaks had increased 10-fold from 167 in 2001 to 1723 in 2007, although most of these outbreaks were rapidly brought under control with an attack rate of less than 10%. HFMD remains an important public health problem in Singapore with the annual incidence rate per 100,000 population increasing from 125.5 in 2001 to 435.9 in 2007, despite stringent measures taken in preschool centres to prevent the transmission of infection. A high degree of vigilance should be maintained over the disease situation, in particular, surveillance of EV 71 which continues to cause severe complications and deaths in the region.
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              Neurodevelopment and cognition in children after enterovirus 71 infection.

              Enterovirus 71 is a common cause of hand, foot, and mouth disease and encephalitis in Asia and elsewhere. The long-term neurologic and psychiatric effects of this viral infection on the central nervous system (CNS) are not well understood. We conducted long-term follow-up of 142 children after enterovirus 71 infection with CNS involvement - 61 who had aseptic meningitis, 53 who had severe CNS involvement, and 28 who had cardiopulmonary failure after CNS involvement. At a median follow-up of 2.9 years (range, 1.0 to 7.4) after infection, the children received physical and neurologic examinations. We administered the Denver Developmental Screening Test (DDST II) to children 6 years of age or younger and the Wechsler intelligence test to children 4 years of age or older. Nine of the 16 patients with a poliomyelitis-like syndrome (56%) and 1 of the 5 patients with encephalomyelitis (20%) had sequelae involving limb weakness and atrophy. Eighteen of the 28 patients with cardiopulmonary failure after CNS involvement (64%) had limb weakness and atrophy, 17 (61%) required tube feeding, and 16 (57%) required ventilator support. Among patients who underwent DDST II assessment, delayed neurodevelopment was found in only 1 of 20 patients (5%) with severe CNS involvement and in 21 of 28 patients (75%) with cardiopulmonary failure (P<0.001 for the overall comparison). Children with cardiopulmonary failure after CNS involvement scored lower on intelligence tests than did children with CNS involvement alone (P=0.003). Enterovirus 71 infection with CNS involvement and cardiopulmonary failure may be associated with neurologic sequelae, delayed neurodevelopment, and reduced cognitive functioning. Children with CNS involvement without cardiopulmonary failure did well on neurodevelopment tests. (ClinicalTrials.gov number, NCT00172393 [ClinicalTrials.gov].). Copyright 2007 Massachusetts Medical Society.
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                Author and article information

                Journal
                Virol J
                Virology Journal
                BioMed Central
                1743-422X
                2009
                15 September 2009
                : 6
                : 141
                Affiliations
                [1 ]Kaohsiung American School and Department of Medical Research, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University, Kaohsiung 833, Taiwan, Republic of China
                Article
                1743-422X-6-141
                10.1186/1743-422X-6-141
                2751754
                19751532
                03f4f18e-5f33-49bb-b753-9b495d866d7f
                Copyright © 2009 Yang et al; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 2 July 2009
                : 15 September 2009
                Categories
                Research

                Microbiology & Virology
                Microbiology & Virology

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