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2.
Cell ; 184(17): 4414-4429.e19, 2021 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-34416146

RESUMO

Alphaviruses are emerging, mosquito-transmitted pathogens that cause musculoskeletal and neurological disease in humans. Although neutralizing antibodies that inhibit individual alphaviruses have been described, broadly reactive antibodies that protect against both arthritogenic and encephalitic alphaviruses have not been reported. Here, we identify DC2.112 and DC2.315, two pan-protective yet poorly neutralizing human monoclonal antibodies (mAbs) that avidly bind to viral antigen on the surface of cells infected with arthritogenic and encephalitic alphaviruses. These mAbs engage a conserved epitope in domain II of the E1 protein proximal to and within the fusion peptide. Treatment with DC2.112 or DC2.315 protects mice against infection by both arthritogenic (chikungunya and Mayaro) and encephalitic (Venezuelan, Eastern, and Western equine encephalitis) alphaviruses through multiple mechanisms, including inhibition of viral egress and monocyte-dependent Fc effector functions. These findings define a conserved epitope recognized by weakly neutralizing yet protective antibodies that could be targeted for pan-alphavirus immunotherapy and vaccine design.


Assuntos
Alphavirus/imunologia , Anticorpos Antivirais/imunologia , Sequência Conservada/imunologia , Epitopos/imunologia , Proteínas Virais/imunologia , Infecções por Alphavirus/imunologia , Infecções por Alphavirus/virologia , Sequência de Aminoácidos , Animais , Anticorpos Monoclonais/imunologia , Febre de Chikungunya/imunologia , Febre de Chikungunya/virologia , Vírus Chikungunya/imunologia , Chlorocebus aethiops , Mapeamento de Epitopos , Epitopos/química , Humanos , Masculino , Camundongos Endogâmicos C57BL , Modelos Biológicos , Monócitos/metabolismo , Células Vero , Proteínas Virais/química , Liberação de Vírus
3.
Nature ; 588(7837): 308-314, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33208938

RESUMO

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.


Assuntos
Vírus da Encefalite Equina Venezuelana/metabolismo , Receptores de LDL/metabolismo , Receptores Virais/metabolismo , Animais , Sistemas CRISPR-Cas/genética , Linhagem Celular , Vírus da Encefalite Equina Venezuelana/patogenicidade , Encefalomielite Equina Venezuelana/metabolismo , Encefalomielite Equina Venezuelana/prevenção & controle , Encefalomielite Equina Venezuelana/virologia , Feminino , Teste de Complementação Genética , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ligação Proteica , Receptores de LDL/deficiência , Receptores de LDL/genética , Receptores Virais/genética , Ligação Viral , Internalização do Vírus
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