Vincent Le Moigne1, Martin Rottman1, Céline Goulard1, Benoît Barteau2, Isabelle Poncin3, Nathalie Soismier1, Stéphane Canaan3, Bruno Pitard4, Jean-Louis Gaillard1, Jean-Louis Herrmann5. 1. INSERM U1173, UFR Simone Veil, Versailles-Saint-Quentin University, 78180 Saint-Quentin en Yvelines, France. 2. IN-CELL-ART, Nantes, France. 3. CNRS-Aix-Marseille Université-Enzymologie Interfaciale et Physiologie de la Lipolyse UMR 7282, 31 chemin Joseph Aiguier, 13402 Marseille Cedex 20, France. 4. INSERM UMR 1087, CNRS UMR 6291, Nantes, France; Université de Nantes, l'institut du thorax, Nantes, France. 5. INSERM U1173, UFR Simone Veil, Versailles-Saint-Quentin University, 78180 Saint-Quentin en Yvelines, France. Electronic address: jean-louis.herrmann@rpc.aphp.fr.
Abstract
BACKGROUND: Vaccine strategies represent one of the fighting answers against multiresistant bacteria in a number of clinical settings like cystic fibrosis (CF). Mycobacterium abscessus, an emerging CF pathogen, raises difficult therapeutic problems due to its intrinsic antibiotic multiresistance. METHODS: By reverse vaccinology, we identified M. abscessus phospholipase C (MA-PLC) as a potential vaccine target. We deciphered here the protective response generated by vaccination with plasmid DNA encoding the MA-PLC formulated with a tetra functional block copolymer 704, in CF (ΔF508) mice. Protection was tested against aerosolized smooth and rough (hypervirulent) variants of M. abscessus. RESULTS: MA-PLC DNA vaccination (days 0, 21, 42) elicited a strong antibody response. A significant protective effect was obtained against aerosolized M. abscessus (S variant) in ΔF508 mice, but not in wild-type FVB littermates; similar results were observed when: (i) challenging mice with the "hypervirulent" R variant, and; (ii) immunizing mice with purified MA-PLC protein. High IgG titers against MA-PLC protein were measured in CF patients with M. abscessus infection; interestingly, significant titers were also detected in CF patients positive for Pseudomonas aeruginosa versus P. aeruginosa-negative controls. CONCLUSIONS: MA-PLC DNA- and PLC protein-vaccinated mice cleared more rapidly M. abscessus than β-galactosidase DNA- or PBS- vaccinated mice in the context of CF. PLCs could constitute interesting vaccine targets against common PLC-producing CF pathogens like P. aeruginosa.
BACKGROUND: Vaccine strategies represent one of the fighting answers against multiresistant bacteria in a number of clinical settings like cystic fibrosis (CF). Mycobacterium abscessus, an emerging CF pathogen, raises difficult therapeutic problems due to its intrinsic antibiotic multiresistance. METHODS: By reverse vaccinology, we identified M. abscessus phospholipase C (MA-PLC) as a potential vaccine target. We deciphered here the protective response generated by vaccination with plasmid DNA encoding the MA-PLC formulated with a tetra functional blockcopolymer 704, in CF (ΔF508) mice. Protection was tested against aerosolized smooth and rough (hypervirulent) variants of M. abscessus. RESULTS: MA-PLC DNA vaccination (days 0, 21, 42) elicited a strong antibody response. A significant protective effect was obtained against aerosolized M. abscessus (S variant) in ΔF508 mice, but not in wild-type FVB littermates; similar results were observed when: (i) challenging mice with the "hypervirulent" R variant, and; (ii) immunizing mice with purified MA-PLC protein. High IgG titers against MA-PLC protein were measured in CF patients with M. abscessus infection; interestingly, significant titers were also detected in CF patients positive for Pseudomonas aeruginosa versus P. aeruginosa-negative controls. CONCLUSIONS: MA-PLC DNA- and PLC protein-vaccinated mice cleared more rapidly M. abscessus than β-galactosidase DNA- or PBS- vaccinated mice in the context of CF. PLCs could constitute interesting vaccine targets against common PLC-producing CF pathogens like P. aeruginosa.
Authors: Shelby Daniel-Wayman; Getahun Abate; Daniel L Barber; Luiz E Bermudez; Rhea N Coler; Michael H Cynamon; Charles L Daley; Rebecca M Davidson; Thomas Dick; R Andres Floto; Emily Henkle; Steven M Holland; Mary Jackson; Richard E Lee; Eric L Nuermberger; Kenneth N Olivier; Diane J Ordway; D Rebecca Prevots; James C Sacchettini; Max Salfinger; Christopher M Sassetti; Christine F Sizemore; Kevin L Winthrop; Adrian M Zelazny Journal: Am J Respir Crit Care Med Date: 2019-04-15 Impact factor: 21.405