title: Receptor-activated human α2-macroglobulin interacts with the envelope protein of dengue virus and protects virions from temperature-induced inactivation through multivalent binding.
abstract: Based on the hypothesis that interactions between virions and serum components may influence the outcome of dengue virus (DENV) infections, we decided to use affinity chromatography with domain III from the envelope (E) protein of DENV2 (DIIIE2) as a ligand to isolate virus-binding proteins from human plasma. This approach yielded serum amyloid P (SAP) and α2-macroglobulin (α2M) as novel viral interactors. After confirming the specific binding of both SAP and α2M to DIIIE2 by ELISA, the latter interaction was examined in greater detail. We obtain evidence suggesting that the binding species was actually the receptor-activated form of α2M (α2M*), that α2M* could bind monovalently to recombinant domain III from all four DENV serotypes with affinities in the micromolar range ranking as DENV4>DENV1~DENV2>DENV3 and that this interaction exhibited a strong avidity effect when multivalent binding was favoured (KD 8 × 10(-8) M for DIIIE2). We also showed that α2M* bound to DENV virions of the four serotypes, protecting the virus from temperature-induced inactivation in the absence of serum and enhancing infectivity. The latter effect exhibited an ED50 of 2.9 × 10(-8) M, also suggesting an avidity effect due to multivalent binding. These results will further contribute to the characterization of the virus-host factor interaction network during human DENV infection.
authors.affiliation: Center for Genetic Engineering and Biotechnology (CIGB), PO Box 6162, Havana 10600, Cuba.
authors.forename: Vivian
authors.initials: V
authors.lastname: Huerta
authors.affiliation: Center for Genetic Engineering and Biotechnology (CIGB), PO Box 6162, Havana 10600, Cuba.
authors.forename: Patricia
authors.initials: P
authors.lastname: Toledo
authors.affiliation: Center for Genetic Engineering and Biotechnology (CIGB), PO Box 6162, Havana 10600, Cuba.
authors.forename: Noralvis
authors.initials: N
authors.lastname: Fleitas
authors.affiliation: Center for Genetic Engineering and Biotechnology (CIGB), PO Box 6162, Havana 10600, Cuba.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Martín
authors.affiliation: Center for Genetic Engineering and Biotechnology (CIGB), PO Box 6162, Havana 10600, Cuba.
authors.forename: Dianne
authors.initials: D
authors.lastname: Pupo
authors.affiliation: Center for Genetic Engineering and Biotechnology (CIGB), PO Box 6162, Havana 10600, Cuba.
authors.forename: Alexis
authors.initials: A
authors.lastname: Yero
authors.affiliation: Center for Genetic Engineering and Biotechnology (CIGB), PO Box 6162, Havana 10600, Cuba.
authors.forename: Mónica
authors.initials: M
authors.lastname: Sarría
authors.affiliation: Center for Genetic Engineering and Biotechnology (CIGB), PO Box 6162, Havana 10600, Cuba.
authors.forename: Aniel
authors.initials: A
authors.lastname: Sánchez
authors.affiliation: Center for Genetic Engineering and Biotechnology (CIGB), PO Box 6162, Havana 10600, Cuba.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Besada
authors.affiliation: Center for Genetic Engineering and Biotechnology (CIGB), PO Box 6162, Havana 10600, Cuba.
authors.forename: Yassel
authors.initials: Y
authors.lastname: Ramos
authors.affiliation: Center for Genetic Engineering and Biotechnology (CIGB), PO Box 6162, Havana 10600, Cuba.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Márquez
authors.affiliation: Center for Genetic Engineering and Biotechnology (CIGB), PO Box 6162, Havana 10600, Cuba.
authors.forename: Osmany
authors.initials: O
authors.lastname: Guirola
authors.affiliation: Center for Genetic Engineering and Biotechnology (CIGB), PO Box 6162, Havana 10600, Cuba.
authors.forename: Glay
authors.initials: G
authors.lastname: Chinea
mesh_terms: D000818:Animals; D002522:Chlorocebus aethiops; D003716:Dengue Virus / Q000235:genetics / Q000378:metabolism*; D015967:Gene Expression Regulation, Viral / Q000502:physiology; D022781:Hepatocytes; D006358:Hot Temperature; D006801:Humans; D011485:Protein Binding; D014709:Vero Cells; D014759:Viral Envelope Proteins / Q000737:chemistry / Q000378:metabolism*; D000511:alpha-Macroglobulins
chemical_list: D014759:Viral Envelope Proteins; D000511:alpha-Macroglobulins