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      The M/GP 5 Glycoprotein Complex of Porcine Reproductive and Respiratory Syndrome Virus Binds the Sialoadhesin Receptor in a Sialic Acid-Dependent Manner

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          Abstract

          The porcine reproductive and respiratory syndrome virus (PRRSV) is a major threat to swine health worldwide and is considered the most significant viral disease in the swine industry today. In past years, studies on the entry of the virus into its host cell have led to the identification of a number of essential virus receptors and entry mediators. However, viral counterparts for these molecules have remained elusive and this has made rational development of new generation vaccines impossible. The main objective of this study was to identify the viral counterparts for sialoadhesin, a crucial PRRSV receptor on macrophages. For this purpose, a soluble form of sialoadhesin was constructed and validated. The soluble sialoadhesin could bind PRRSV in a sialic acid-dependent manner and could neutralize PRRSV infection of macrophages, thereby confirming the role of sialoadhesin as an essential PRRSV receptor on macrophages. Although sialic acids are present on the GP 3, GP 4 and GP 5 envelope glycoproteins, only the M/GP 5 glycoprotein complex of PRRSV was identified as a ligand for sialoadhesin. The interaction was found to be dependent on the sialic acid binding capacity of sialoadhesin and on the presence of sialic acids on GP 5. These findings not only contribute to a better understanding of PRRSV biology, but the knowledge and tools generated in this study also hold the key to the development of a new generation of PRRSV vaccines.

          Author Summary

          The porcine reproductive and respiratory syndrome virus (PRRSV) is a major threat to swine health worldwide. The virus specifically targets subpopulations of macrophages, central players in the immune system, and can persist in animals for extended periods of time due to a hampered immunity. At present, no vaccines are available that are both safe and effective and it is clear that a more rational vaccine design is needed to solve this problem. Therefore, advancing our fundamental understanding of PRRSV biology is crucial. The macrophage-specific lectin sialoadhesin is a crucial viral receptor on macrophages and although its role in PRRSV infection is well documented, its viral counterparts have remained unknown. Using a soluble form of sialoadhesin, we identified the M/GP 5 glycoprotein complex of PRRSV as the ligand for sialoadhesin and found this ligand-receptor interaction to be critically dependent on the lectin activity of sialoadhesin and on sialic acids on the GP 5 glycoprotein. These data represent a major breakthrough in the understanding of the role of PRRSV proteins in viral entry and pave the way for the development of a new generation of PRRSV vaccines capable of inducing an immunity that specifically blocks the interaction between viral M/GP 5 and sialoadhesin.

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          Most cited references62

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          Nidovirales: a new order comprising Coronaviridae and Arteriviridae.

          D Cavanagh (1997)
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            Assessment of the economic impact of porcine reproductive and respiratory syndrome on swine production in the United States.

            To estimate the annual cost of infections attributable to porcine reproductive and respiratory syndrome (PRRS) virus to US swine producers. Economic analysis. Data on the health and productivity of PRRS-affected and PRRS-unaffected breeding herds and growing-pig populations were collected from a convenience sample of swine farms in the midwestern United States. Health and productivity variables of PRRS-affected and PRRS-unaffected swine farms were analyzed to estimate the impact of PRRS on specific farms. National estimates of PRRS incidence were then used to determine the annual economic impact of PRRS on US swine producers. PRRS affected breeding herds and growing-pig populations as measured by a decrease in reproductive health, an increase in deaths, and reductions in the rate and efficiency of growth. Total annual economic impact of these effects on US swine producers was estimated at dollar 66.75 million in breeding herds and dollar 493.57 million in growing-pig populations. PRRS imposes a substantial financial burden on US swine producers and causes approximately dollar 560.32 million in losses each year. By comparison, prior to eradication, annual losses attributable to classical swine fever (hog cholera) and pseudorabies were estimated at dollar 364.09 million and dollar 36.27 million, respectively (adjusted on the basis of year 2004 dollars). Current PRRS control strategies are not predictably successful; thus, PRRS-associated losses will continue into the future. Research to improve our understanding of ecologic and epidemiologic characteristics of the PRRS virus and technologic advances (vaccines and diagnostic tests) to prevent clinical effects are warranted.
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              Lelystad Virus, the Causative Agent of Porcine Epidemic Abortion and Respiratory Syndrome (PEARS), Is Related to LDV and EAV

              The genome of Lelystad virus (LV), the causative agent of porcine epidemic abortion and respiratory syndrome (previously known as mystery swine disease), was shown to be a polyadenylated RNA molecule. The nucleotide sequence of the LV genome was determined from a set of overlapping cDNA clones. A consecutive sequence of 15,088 nucleotides was obtained. Eight open reading frames (ORFs) that might encode virus-specific proteins were identified. ORF1a and ORF1b are predicted to encode the vital RNA polymerase because the amino acid sequence contains sequence elements that are conserved in RNA polymerases of the torovirus Berne virus (BEV), equine arteritis virus (EAV), lactate dehydrogenase-elevating virus (LDV), the coronaviruses, and other positive-strand RNA viruses. A heptanucleotide slippery sequence (UUUAAAC) and a putative pseudoknot structure, which are both required for efficient ribosomal frameshifting during translation of the RNA polymerase ORF 1b of BEV, EAV, and the coronaviruses, were identified in the overlapping region of ORF1a and ORF1b of LV. ORFs 2 to 6 probably encode viral membrane-associated proteins, whereas ORF7 is predicted to encode the nucleocapsid protein. Comparison of the amino acid sequences of the ORFs identified in the genome of LV, LDV, and EAV indicated that LV and LDV are more closely related than LV and EAV. A 3′ nested set of six subgenomic RNAs was detected in LV-infected cells. These subgenomic RNAs contain a common leader sequence that is derived from the 5′ end of the genomic RNA and that is joined to the 3′ terminal body sequence. Our results indicate that LV is closely related evolutionarily to LDV and EAV, both members of a recently proposed family of positive-strand RNA viruses, the Arteriviridae.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Pathog
                plos
                plospath
                PLoS Pathogens
                Public Library of Science (San Francisco, USA )
                1553-7366
                1553-7374
                January 2010
                January 2010
                15 January 2010
                : 6
                : 1
                : e1000730
                Affiliations
                [1 ]Laboratory of Virology, Department of Virology, Parasitology and Immunology, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium
                [2 ]Division of Cell Biology and Immunology, Wellcome Trust Biocentre, University of Dundee, Dundee, United Kingdom
                University of Washington, United States of America
                Author notes

                Conceived and designed the experiments: WVB PRC PLD HJN. Performed the experiments: WVB HVG JQZ PLD. Analyzed the data: WVB JQZ PRC PLD HJN. Wrote the paper: WVB PLD.

                ¶ These authors share senior authorship.

                Article
                09-PLPA-RA-0770R2
                10.1371/journal.ppat.1000730
                2799551
                20084110
                7c2424c6-f138-4453-959b-1f3c28572a02
                Van Breedam et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 12 May 2009
                : 16 December 2009
                Page count
                Pages: 11
                Categories
                Research Article
                Infectious Diseases/Viral Infections
                Microbiology/Cellular Microbiology and Pathogenesis
                Virology/Host Invasion and Cell Entry

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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