title: Lentiviral Vector Gene Therapy Protects XCGD Mice From Acute Staphylococcus aureus Pneumonia and Inflammatory Response.
abstract: Chronic granulomatous disease (CGD) is a primary immunodeficiency due to a deficiency in one of the subunits of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. CGD patients are characterized by an increased susceptibility to bacterial and fungal infections, and to granuloma formation due to the excessive inflammatory responses. Several gene therapy approaches with lentiviral vectors have been proposed but there is a lack of in vivo data on the ability to control infections and inflammation. We set up a mouse model of acute infection that closely mimic the airway infection in CGD patients. It involved an intratracheal injection of a methicillin-sensitive reference strain of S. aureus. Gene therapy, with hematopoietic stem cells transduced with regulated lentiviral vectors, restored the functional activity of NADPH oxidase complex (with 20-98% of dihydrorhodamine positive granulocytes and monocytes) and saved mice from death caused by S. aureus, significantly reducing the bacterial load and lung damage, similarly to WT mice even at low vector copy number. When challenged, gene therapy-treated XCGD mice showed correction of proinflammatory cytokines and chemokine imbalance at levels that were comparable to WT. Examined together, our results support the clinical development of gene therapy protocols using lentiviral vectors for the protection against infections and inflammation.
authors.affiliation: San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Giada
authors.initials: G
authors.lastname: Farinelli
authors.affiliation: San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Raisa
authors.initials: R
authors.lastname: Jofra Hernandez
authors.affiliation: Infection and Cystic Fibrosis Unit, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Alice
authors.initials: A
authors.lastname: Rossi
authors.affiliation: Infection and Cystic Fibrosis Unit, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Ranucci
authors.affiliation: Pathology Unit, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Sanvito
authors.affiliation: San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), San Raffaele Scientific Institute, Milan, Italy.|Pediatric Immunohematology and Bone Marrow Transplantation Unit, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Maddalena
authors.initials: M
authors.lastname: Migliavacca
authors.affiliation: CUSSB-University Center Center for Statistics in the Biomedical Sciences, Vita-Salute San Raffaele University, Milan, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Brombin
authors.affiliation: CUSSB-University Center Center for Statistics in the Biomedical Sciences, Vita-Salute San Raffaele University, Milan, Italy.
authors.forename: Aleksandar
authors.initials: A
authors.lastname: Pramov
authors.affiliation: CUSSB-University Center Center for Statistics in the Biomedical Sciences, Vita-Salute San Raffaele University, Milan, Italy.
authors.forename: Clelia
authors.initials: C
authors.lastname: Di Serio
authors.affiliation: MolMed S.p.A., Milano, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Bovolenta
authors.affiliation: San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), San Raffaele Scientific Institute, Milan, Italy.|Haematology and Bone Marrow Transplantation Unit, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Gentner
authors.affiliation: Infection and Cystic Fibrosis Unit, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bragonzi
authors.affiliation: San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), San Raffaele Scientific Institute, Milan, Italy.|Pediatric Immunohematology and Bone Marrow Transplantation Unit, San Raffaele Scientific Institute, Milan, Italy.|Vita-Salute San Raffaele University, Milan, Italy, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Aiuti
mesh_terms: D000818:Animals; D058491:Bacterial Load; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage; D006105:Granulomatous Disease, Chronic / Q000150:complications* / Q000235:genetics; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006412:Hematopoietic Stem Cells / Q000821:virology; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D008562:Membrane Glycoproteins / Q000235:genetics*; D051379:Mice; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics*; D011023:Pneumonia, Staphylococcal / Q000235:genetics / Q000382:microbiology / Q000628:therapy*; D013211:Staphylococcus aureus / Q000502:physiology*
chemical_list: D018925:Chemokines; D016207:Cytokines; D008562:Membrane Glycoproteins; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases