Host receptor-targeted therapeutic approach to counter pathogenic New World mammarenavirus infections
Copyright policy )Host receptor-targeted therapeutic approach to counter pathogenic New World mammarenavirus infections
AbstractFive 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.
- University of California, San Francisco United States
- Department of Microbiology United States
- National Scientific and Technical Research Council Argentina
- United States Food and Drug Administration United States
- UCLA Jonsson Comprehensive Cancer Center United States
Fragment crystallizable region, Pathogenesis, FOS: Health sciences, Inbred C57BL, Biochemistry, Transgenic, Mice, Viral Envelope Proteins, https://purl.org/becyt/ford/3.4, Monoclonal, Receptors, https://purl.org/becyt/ford/3.1, Chlorocebus aethiops, 2.1 Biological and endogenous factors, Aetiology, Arenaviridae, Q, Transferrin, Antibodies, Monoclonal, Ebola Virus Research and Outbreaks, Life Sciences, DRUG EFFECTS, THERAPEUTIC, CD, Molecular Docking Simulation, Chemistry, Infectious Diseases, Medical Microbiology, 5.1 Pharmaceuticals, Host-Pathogen Interactions, Medicine, Development of treatments and therapeutic interventions, Infection, Protein Binding, Receptor, Monoclonal antibody, 570, Transferrin receptor, Science, Immunology, Docking (animal), 610, Mice, Transgenic, Nursing, Antibodies, HOST PATHOGEN INTERACTIONS, Article, Hemorrhagic Fever, American, Vaccine Related, In vitro, Antigens, CD, Biodefense, Biochemistry, Genetics and Molecular Biology, Virology, Receptors, Transferrin, Health Sciences, Genetics, Animals, Humans, https://purl.org/becyt/ford/3, Antigens, Vero Cells, Biology, MONOCLONAL, Antibody, Junin virus, Biomedical and Clinical Sciences, Prevention, FOS: Clinical medicine, Gastrointestinal Viral Infections and Vaccines Development, Mice, Inbred C57BL, Emerging Infectious Diseases, ANTIBODY, A549 Cells, FOS: Biological sciences, HEMORRHAGIC FEVER, AMERICAN, Hemorrhagic Fever, Gene Therapy Techniques and Applications, American, JUNIN VIRUS
Fragment crystallizable region, Pathogenesis, FOS: Health sciences, Inbred C57BL, Biochemistry, Transgenic, Mice, Viral Envelope Proteins, https://purl.org/becyt/ford/3.4, Monoclonal, Receptors, https://purl.org/becyt/ford/3.1, Chlorocebus aethiops, 2.1 Biological and endogenous factors, Aetiology, Arenaviridae, Q, Transferrin, Antibodies, Monoclonal, Ebola Virus Research and Outbreaks, Life Sciences, DRUG EFFECTS, THERAPEUTIC, CD, Molecular Docking Simulation, Chemistry, Infectious Diseases, Medical Microbiology, 5.1 Pharmaceuticals, Host-Pathogen Interactions, Medicine, Development of treatments and therapeutic interventions, Infection, Protein Binding, Receptor, Monoclonal antibody, 570, Transferrin receptor, Science, Immunology, Docking (animal), 610, Mice, Transgenic, Nursing, Antibodies, HOST PATHOGEN INTERACTIONS, Article, Hemorrhagic Fever, American, Vaccine Related, In vitro, Antigens, CD, Biodefense, Biochemistry, Genetics and Molecular Biology, Virology, Receptors, Transferrin, Health Sciences, Genetics, Animals, Humans, https://purl.org/becyt/ford/3, Antigens, Vero Cells, Biology, MONOCLONAL, Antibody, Junin virus, Biomedical and Clinical Sciences, Prevention, FOS: Clinical medicine, Gastrointestinal Viral Infections and Vaccines Development, Mice, Inbred C57BL, Emerging Infectious Diseases, ANTIBODY, A549 Cells, FOS: Biological sciences, HEMORRHAGIC FEVER, AMERICAN, Hemorrhagic Fever, Gene Therapy Techniques and Applications, American, JUNIN VIRUS
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