title: Liposomes loaded with bioactive lipids enhance antibacterial innate immunity irrespective of drug resistance.
abstract: Phagocytosis is a key mechanism of innate immunity, and promotion of phagosome maturation may represent a therapeutic target to enhance antibacterial host response. Phagosome maturation is favored by the timely and coordinated intervention of lipids and may be altered in infections. Here we used apoptotic body-like liposomes (ABL) to selectively deliver bioactive lipids to innate cells, and then tested their function in models of pathogen-inhibited and host-impaired phagosome maturation. Stimulation of macrophages with ABLs carrying phosphatidic acid (PA), phosphatidylinositol 3-phosphate (PI3P) or PI5P increased intracellular killing of BCG, by inducing phagosome acidification and ROS generation. Moreover, ABLs carrying PA or PI5P enhanced ROS-mediated intracellular killing of Pseudomonas aeruginosa, in macrophages expressing a pharmacologically-inhibited or a naturally-mutated cystic fibrosis transmembrane conductance regulator. Finally, we show that bronchoalveolar lavage cells from patients with drug-resistant pulmonary infections increased significantly their capacity to kill in vivo acquired bacterial pathogens when ex vivo stimulated with PA- or PI5P-loaded ABLs. Altogether, these results provide the proof of concept of the efficacy of bioactive lipids delivered by ABL to enhance phagosome maturation dependent antimicrobial response, as an additional host-directed strategy aimed at the control of chronic, recurrent or drug-resistant infections.
authors.affiliation: Department of Biology, University of Rome Tor Vergata Rome, Italy.
authors.forename: Noemi
authors.initials: N
authors.lastname: Poerio
authors.affiliation: Institute of Microbiology, Fondazione Policlinico Universitario Gemelli - Catholic University of Sacred Heart, Rome, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Bugli
authors.affiliation: Department of Biology, University of Rome Tor Vergata Rome, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Taus
authors.affiliation: Department of Biology, University of Rome Tor Vergata Rome, Italy.
authors.forename: Marilina B
authors.initials: MB
authors.lastname: Santucci
authors.affiliation: Department of Biology, University of Rome Tor Vergata Rome, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Rodolfo
authors.affiliation: Department of Biology, University of Rome Tor Vergata Rome, Italy.|Unit of Cell Stress and Survival, Danish Cancer Society Research Center, Copenhagen, Denmark.|Department of Pediatric Hematology and Oncology, IRCCS Bambino Gesù Children's Hospital, Rome, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Cecconi
authors.affiliation: Institute of Microbiology, Fondazione Policlinico Universitario Gemelli - Catholic University of Sacred Heart, Rome, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Torelli
authors.affiliation: Department of Pulmonary Medicine, Fondazione Policlinico Universitario Gemelli - Catholic University of Sacred Heart, Rome, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Varone
authors.affiliation: Department of Pulmonary Medicine, Fondazione Policlinico Universitario Gemelli - Catholic University of Sacred Heart, Rome, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Inchingolo
authors.affiliation: Cystic Fibrosis Unit, Paediatric Hospital "Bambino Gesù", Rome, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Majo
authors.affiliation: Cystic Fibrosis Unit, Paediatric Hospital "Bambino Gesù", Rome, Italy.
authors.forename: Vincenzina
authors.initials: V
authors.lastname: Lucidi
authors.affiliation: Department of Infectious, Parasitic and Immunomediated Diseases, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Mariotti
authors.affiliation: Department of Infectious, Parasitic and Immunomediated Diseases, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Nisini
authors.affiliation: Institute of Microbiology, Fondazione Policlinico Universitario Gemelli - Catholic University of Sacred Heart, Rome, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Sanguinetti
authors.affiliation: Department of Biology, University of Rome Tor Vergata Rome, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Fraziano
mesh_terms: D000293:Adolescent; D000328:Adult; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002648:Child; D024881:Drug Resistance, Bacterial; D005260:Female; D006801:Humans; D007113:Immunity, Innate; D008081:Liposomes; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D008297:Male; D010587:Phagocytosis; D010588:Phagosomes / Q000187:drug effects / Q000276:immunology; D018129:Phosphatidylinositol Phosphates / Q000008:administration & dosage / Q000276:immunology* / Q000494:pharmacology; D011550:Pseudomonas aeruginosa / Q000276:immunology
chemical_list: D008081:Liposomes; D018129:Phosphatidylinositol Phosphates