Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 3 de 3
Filtrar
Más filtros











Base de datos
Intervalo de año de publicación
1.
Nature ; 598(7882): 672-676, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34646020

RESUMEN

LDLRAD3 is a recently defined attachment and entry receptor for Venezuelan equine encephalitis virus (VEEV)1, a New World alphavirus that causes severe neurological disease in humans. Here we present near-atomic-resolution cryo-electron microscopy reconstructions of VEEV virus-like particles alone and in a complex with the ectodomains of LDLRAD3. Domain 1 of LDLRAD3 is a low-density lipoprotein receptor type-A module that binds to VEEV by wedging into a cleft created by two adjacent E2-E1 heterodimers in one trimeric spike, and engages domains A and B of E2 and the fusion loop in E1. Atomic modelling of this interface is supported by mutagenesis and anti-VEEV antibody binding competition assays. Notably, VEEV engages LDLRAD3 in a manner that is similar to the way that arthritogenic alphaviruses bind to the structurally unrelated MXRA8 receptor, but with a much smaller interface. These studies further elucidate the structural basis of alphavirus-receptor interactions, which could inform the development of therapies to mitigate infection and disease against multiple members of this family.


Asunto(s)
Virus de la Encefalitis Equina Venezolana/química , Receptores de LDL/química , Receptores Virales/química , Secuencia de Aminoácidos , Animales , Línea Celular , Microscopía por Crioelectrón , Humanos , Ratones , Modelos Moleculares , Estructura Secundaria de Proteína , Alineación de Secuencia , Internalización del Virus
2.
Nature ; 588(7837): 308-314, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-33208938

RESUMEN

Venezuelan equine encephalitis virus (VEEV) is a neurotropic alphavirus transmitted by mosquitoes that causes encephalitis and death in humans1. VEEV is a biodefence concern because of its potential for aerosol spread and the current lack of sufficient countermeasures. The host factors that are required for VEEV entry and infection remain poorly characterized. Here, using a genome-wide CRISPR-Cas9-based screen, we identify low-density lipoprotein receptor class A domain-containing 3 (LDLRAD3)-a highly conserved yet poorly characterized member of the scavenger receptor superfamily-as a receptor for VEEV. Gene editing of mouse Ldlrad3 or human LDLRAD3 results in markedly reduced viral infection of neuronal cells, which is restored upon complementation with LDLRAD3. LDLRAD3 binds directly to VEEV particles and enhances virus attachment and internalization into host cells. Genetic studies indicate that domain 1 of LDLRAD3 (LDLRAD3(D1)) is necessary and sufficient to support infection by VEEV, and both anti-LDLRAD3 antibodies and an LDLRAD3(D1)-Fc fusion protein block VEEV infection in cell culture. The pathogenesis of VEEV infection is abrogated in mice with deletions in Ldlrad3, and administration of LDLRAD3(D1)-Fc abolishes disease caused by several subtypes of VEEV, including highly virulent strains. The development of a decoy-receptor fusion protein suggests a strategy for the prevention of severe VEEV infection and associated disease in humans.


Asunto(s)
Virus de la Encefalitis Equina Venezolana/metabolismo , Receptores de LDL/metabolismo , Receptores Virales/metabolismo , Animales , Sistemas CRISPR-Cas/genética , Línea Celular , Virus de la Encefalitis Equina Venezolana/patogenicidad , Encefalomielitis Equina Venezolana/metabolismo , Encefalomielitis Equina Venezolana/prevención & control , Encefalomielitis Equina Venezolana/virología , Femenino , Prueba de Complementación Genética , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Unión Proteica , Receptores de LDL/deficiencia , Receptores de LDL/genética , Receptores Virales/genética , Acoplamiento Viral , Internalización del Virus
3.
J Virol ; 88(1): 538-46, 2014 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-24173234

RESUMEN

Viruses have long been studied not only for their pathology and associated disease but also as model systems for understanding cellular and immunological processes. Rodent herpesvirus Peru (RHVP) is a recently characterized rhadinovirus related to murine gammaherpesvirus 68 (MHV68) and Kaposi's sarcoma-associated herpesvirus (KSHV) that establishes acute and latent infection in laboratory mice. RHVP encodes numerous unique proteins that we hypothesize might facilitate host immune evasion during infection. We report here that open reading frame (ORF) R17 encodes a high-affinity chemokine binding protein that broadly recognizes human and murine CC and C chemokines. The interaction of R17 with chemokines is generally characterized by rapid association kinetics, and in the case of CCL3, CCL4, CCL5, CCL24, and XCL1, extremely stable complexes are formed. Functionally, R17 potently inhibited CCL2-driven chemotaxis of the human monocytic cell line THP-1, CCL3-driven chemotaxis of peripheral blood mononuclear cells, and CCL2-mediated calcium flux. Our studies also reveal that R17 binds to glycosaminoglycans (GAGs) in a process dependent upon two BBXB motifs and that chemokine and GAG binding can occur simultaneously at distinct sites. Collectively, these studies suggest that R17 may play a role in RHVP immune evasion through the targeted sabotage of chemokine-mediated immune surveillance.


Asunto(s)
Receptores de Quimiocina/genética , Rhadinovirus/genética , Animales , Calcio/metabolismo , Quimiocinas/metabolismo , Quimiotaxis de Leucocito , Células HEK293 , Humanos , Ratones , Sistemas de Lectura Abierta , Receptores de Quimiocina/metabolismo , Resonancia por Plasmón de Superficie
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA