Host receptor-targeted therapeutic approach to counter pathogenic New World mammarenavirus infections

Five New World mammarenaviruses (NWMs) cause life-threatening hemorrhagic fever (HF). Cellular entry by these viruses is mediated by human transferrin receptor 1 (hTfR1). Here, we demonstrate that an antibody (ch128.1/IgG1) which binds the apical domain of hTfR1, potently inhibits infection of atten...

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Detalles Bibliográficos
Autores: Hickerson, Brady T., Daniels Wells, Tracy R., Payés, Cristian, Clark, Lars E., Candelaria, Pierre V., Bailey, Kevin W., Sefing, Eric J., Zink, Samantha, Ziegenbein, James, Abraham, Jonathan, Helguera, Gustavo Fernando, Penichet, Manuel L., Gowen, Brian
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2022
País:Argentina
Institución:Consejo Nacional de Investigaciones Científicas y Técnicas
Repositorio:CONICET Digital (CONICET)
Idioma:inglés
OAI Identifier:oai:ri.conicet.gov.ar:11336/166192
Acceso en línea:http://hdl.handle.net/11336/166192
Access Level:acceso abierto
Palabra clave:MONOCLONAL
ANTIBODY
JUNIN VIRUS
THERAPEUTIC
HEMORRHAGIC FEVER, AMERICAN
HOST PATHOGEN INTERACTIONS
DRUG EFFECTS
https://purl.org/becyt/ford/3.4
https://purl.org/becyt/ford/3
https://purl.org/becyt/ford/3.1
Descripción
Sumario:Five New World mammarenaviruses (NWMs) cause life-threatening hemorrhagic fever (HF). Cellular entry by these viruses is mediated by human transferrin receptor 1 (hTfR1). Here, we demonstrate that an antibody (ch128.1/IgG1) which binds the apical domain of hTfR1, potently inhibits infection of attenuated and pathogenic NWMs in vitro. Computational docking of the antibody Fab crystal structure onto the known structure of hTfR1 shows an overlapping receptor-binding region shared by the Fab and the viral envelope glycoprotein GP1 subunit that binds hTfR1, and we demonstrate competitive inhibition of NWM GP1 binding by ch128.1/IgG1 as the principal mechanism of action. Importantly, ch128.1/IgG1 protects hTfR1-expressing transgenic mice against lethal NWM challenge. Additionally, the antibody is well-tolerated and only partially reduces ferritin uptake. Our findings provide the basis for the development of a novel, host receptor-targeted antibody therapeutic broadly applicable to the treatment of HF of NWM etiology.

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