Discovery of highly neutralizing human antibodies targeting Pseudomonas aeruginosa

Cell. 2023 Nov 9;186(23):5098-5113.e19. doi: 10.1016/j.cell.2023.10.002. Epub 2023 Nov 1.

Abstract

Drug-resistant Pseudomonas aeruginosa (PA) poses an emerging threat to human health with urgent need for alternative therapeutic approaches. Here, we deciphered the B cell and antibody response to the virulence-associated type III secretion system (T3SS) in a cohort of patients chronically infected with PA. Single-cell analytics revealed a diverse B cell receptor repertoire directed against the T3SS needle-tip protein PcrV, enabling the production of monoclonal antibodies (mAbs) abrogating T3SS-mediated cytotoxicity. Mechanistic studies involving cryoelectron microscopy identified a surface-exposed C-terminal PcrV epitope as the target of highly neutralizing mAbs with broad activity against drug-resistant PA isolates. These anti-PcrV mAbs were as effective as treatment with conventional antibiotics in vivo. Our study reveals that chronically infected patients represent a source of neutralizing antibodies, which can be exploited as therapeutics against PA.

Keywords: Pseudomonas aeruginosa; anti-virulence therapy; antibacterial antibodies; antimicrobial resistance; monoclonal antibodies; patient-derived antibodies; type III secretion system.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Bacterial* / pharmacology
  • Antibodies, Neutralizing*
  • Cryoelectron Microscopy
  • Humans
  • Immunoglobulins / metabolism
  • Pseudomonas Infections* / drug therapy
  • Pseudomonas aeruginosa* / drug effects
  • Pseudomonas aeruginosa* / physiology

Substances

  • Antibodies, Bacterial
  • Immunoglobulins
  • Antibodies, Neutralizing