期刊
NATURE COMMUNICATIONS
卷 13, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41467-021-27949-3
关键词
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资金
- National Institutes of Health (NIH) [R01CA196266, R21AI135851]
- Programa Bec.Ar
- Fundacion Rene Baron
- Fundacion Bunge y Born
- Fundacion Williams
- National Institute of General Medical Sciences, NIH [P30 GM124165]
- Office of Research Infrastructure Programs (ORIP) High-End Instrumentation (HEI) NIH grant [S10OD021527]
- Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science User Facility [DE-AC02-06CH11357]
- NIH-NIGMS [P41 GM103403]
The study shows that hTfR1-targeting antibodies can partially protect transgenic mice from lethal New World mammarenavirus infection by competing with the viral glycoprotein for hTfR1 binding. This finding has important implications for the treatment of hemorrhagic fever.
Five New World mammarenaviruses (NWMs) enter cells via binding to human transferrin receptor 1 (hTfR1). Here, Hickerson et al. show that hTfR1 targeting antibodies partially protect hTfR1-transgenic mice from lethal NWM challenge via competition of anti-hTfR1 antibody and viral glycoprotein for hTfR1. 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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