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

Nat Commun. 2022 Jan 28;13(1):558. doi: 10.1038/s41467-021-27949-3.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • A549 Cells
  • Animals
  • Antibodies, Monoclonal / immunology
  • Antibodies, Monoclonal / metabolism
  • Antibodies, Monoclonal / pharmacology
  • Antigens, CD / immunology
  • Antigens, CD / metabolism*
  • Arenaviridae / drug effects
  • Arenaviridae / metabolism*
  • Arenaviridae / physiology
  • Chlorocebus aethiops
  • Hemorrhagic Fever, American / metabolism*
  • Hemorrhagic Fever, American / prevention & control
  • Hemorrhagic Fever, American / virology
  • Host-Pathogen Interactions / drug effects
  • Humans
  • Junin virus / drug effects
  • Junin virus / physiology
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Molecular Docking Simulation
  • Protein Binding / drug effects
  • Receptors, Transferrin / antagonists & inhibitors
  • Receptors, Transferrin / immunology
  • Receptors, Transferrin / metabolism*
  • Vero Cells
  • Viral Envelope Proteins / metabolism*

Substances

  • Antibodies, Monoclonal
  • Antigens, CD
  • CD71 antigen
  • Receptors, Transferrin
  • Viral Envelope Proteins