| Title: |
Neutralizing human monoclonal antibodies that target the PcrV component of the type III secretion system of Pseudomonas aeruginosa act through distinct mechanisms |
| Authors: |
Desveaux, Jean-Mathieu; Faudry, Eric; Contreras-Martel, Carlos; Cretin, François; Dergan-Dylon, Leonardo Sebastian; Amen, Axelle; Bally, Isabelle; Tardivy-Casemajor, Victor; Chenavier, Fabien; Fouquenet, Delphine; Caspar, Yvan; Attree, Ina; Dessen, Andrea; Poignard, Pascal |
| Contributors: |
Institut de biologie structurale (IBS - UMR 5075); Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG); Direction de Recherche Fondamentale (CEA) (DRF (CEA)); Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)); Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA); Groupe Pathogenèse Bactérienne et Réponses Cellulaires / Bacterial Pathogenesis and Cellular Responses Group (IBS-PBRC); Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG); CHU de Grenoble-Alpes - Centre Hospitalier Universitaire CHU Grenoble (CHUGA); Centre d’Etude des Pathologies Respiratoires Tours (CEPR - U 1100); Université de Tours (UT); NEOLAiA European University = Université Européenne NEOLAÏA (NEOLAiA)-NEOLAiA European University = Université Européenne NEOLAÏA (NEOLAiA)-Institut National de la Santé et de la Recherche Médicale (INSERM); SPR facility of ISBG; ANR-22-CE18-0009,HUMABACT,Anticorps monoclonaux humains thérapeutiques contre les bactéries multirésistantes par identification de cibles, isolement d'anticorps à partir de cellules B uniques et biologie structurale(2022) |
| Source: |
EISSN: 2050-084X ; eLife ; https://hal.science/hal-05518877 ; eLife, 2026, 14, pp.RP105195. ⟨10.7554/eLife.105195.3⟩ |
| Publisher Information: |
CCSD; eLife Sciences Publication |
| Publication Year: |
2026 |
| Collection: |
Université François-Rabelais de Tours: HAL |
| Subject Terms: |
[SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases; [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry; Molecular Biology/Structural Biology [q-bio.BM]; [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy; [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology |
| Description: |
International audience ; Pseudomonas aeruginosa is a major human opportunistic pathogen associated with a high incidence of multi-drug resistance. The antibody-based blockade of P. aeruginosa virulence factors represents a promising alternative strategy to mitigate its infectivity. In this study, we employed single B cell sorting from cystic fibrosis patients to isolate human monoclonal antibodies (mAbs) targeting proteins from the P. aeruginosa Type 3 Secretion System (T3SS) and characterized a panel of mAbs directed at PscF and PcrV. Among those, two mAbs, P5B3 and P3D6, that bind to the injectisome tip protein PcrV, exhibited T3SS blocking activity. We solved the crystal structure of the P3D6 Fab-PcrV complex, which revealed that the Ab binds to the C-terminal region of PcrV. In addition, we compared the T3SS-blocking activity of three PcrV-targeting mAbs, including two from previous independent studies, using two distinct assays to evaluate pore formation and toxin injection. We conducted a mechanistic and structural analysis of their modes of action through modeling based on the known structure of a functional homolog, SipD from Salmonella typhimurium . The analysis suggests that anti-PcrV mAbs may act through different mechanisms, ranging from preventing PcrV oligomerization to disrupting PcrV’s scaffolding function, thereby inhibiting the assembly and function of the translocon pore. Our findings provide additional evidence that T3SS-targeting Abs, some capable of inhibiting virulence, are elicited in P. aeruginosa -infected patients. The results offer deeper insights into PcrV recognition by mAbs and their associated mechanisms of action, helping to identify which Abs are more likely to be therapeutically useful based on their mode of action and potency. This paves the way for the development of effective alternatives to traditional antibiotics in the fight against this resilient pathogen. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| DOI: |
10.7554/eLife.105195.3 |
| Availability: |
https://hal.science/hal-05518877; https://hal.science/hal-05518877v2/document; https://hal.science/hal-05518877v2/file/Desveaux%20et%20al.%20elife.pdf; https://doi.org/10.7554/eLife.105195.3 |
| Rights: |
https://creativecommons.org/licenses/by/4.0/ ; info:eu-repo/semantics/OpenAccess |
| Accession Number: |
edsbas.F9AB8C5D |
| Database: |
BASE |