title: MgtC as a Host-Induced Factor and Vaccine Candidate against Mycobacterium abscessus Infection.
abstract: Mycobacterium abscessus is an emerging pathogenic mycobacterium involved in pulmonary and mucocutaneous infections, presenting a serious threat for patients with cystic fibrosis (CF). The lack of an efficient treatment regimen and the emergence of multidrug resistance in clinical isolates require the development of new therapeutic strategies against this pathogen. Reverse genetics has revealed genes that are present in M. abscessus but absent from saprophytic mycobacteria and that are potentially involved in pathogenicity. Among them, MAB_3593 encodes MgtC, a known virulence factor involved in intramacrophage survival and adaptation to Mg(2+) deprivation in several major bacterial pathogens. Here, we demonstrated a strong induction of M. abscessus MgtC at both the transcriptional and translational levels when bacteria reside inside macrophages or upon Mg(2+) deprivation. Moreover, we showed that M. abscessus MgtC was recognized by sera from M. abscessus-infected CF patients. The intramacrophage growth (J774 or THP1 cells) of a M. abscessus knockout mgtC mutant was, however, not significantly impeded. Importantly, our results indicated that inhibition of MgtC in vivo through immunization with M. abscessus mgtC DNA, formulated with a tetrafunctional amphiphilic block copolymer, exerted a protective effect against an aerosolized M. abscessus challenge in CF (ΔF508 FVB) mice. The formulated DNA immunization was likely associated with the production of specific MgtC antibodies, which may stimulate a protective effect by counteracting MgtC activity during M. abscessus infection. These results emphasize the importance of M. abscessus MgtC in vivo and provide a basis for the development of novel therapeutic tools against pulmonary M. abscessus infections in CF patients.
authors.affiliation: INSERM, U1173, UFR Simone Veil, Université de Versailles Saint Quentin, Saint Quentin en Yvelines, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Le Moigne
authors.affiliation: Laboratoire de Dynamique des Interactions Membranaires Normales et Pathologiques, Université de Montpellier, Montpellier, France CNRS, UMR5235, Montpellier, France.
authors.forename: Claudine
authors.initials: C
authors.lastname: Belon
authors.affiliation: INSERM, U1173, UFR Simone Veil, Université de Versailles Saint Quentin, Saint Quentin en Yvelines, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Goulard
authors.affiliation: Laboratoire de Dynamique des Interactions Membranaires Normales et Pathologiques, Université de Montpellier, Montpellier, France CNRS, UMR5235, Montpellier, France.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Accard
authors.affiliation: Centre d'études d'agents Pathogènes et Biotechnologies pour la Santé (CPBS), CNRS FRE 3689, Montpellier, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Bernut
authors.affiliation: IN-CELL-ART, Nantes, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Pitard
authors.affiliation: INSERM, U1173, UFR Simone Veil, Université de Versailles Saint Quentin, Saint Quentin en Yvelines, France APHP, Groupe Hospitalo-Universitaire Paris Île-de-France Ouest, Garches et Boulogne-Billancourt, France.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Gaillard
authors.affiliation: Centre d'études d'agents Pathogènes et Biotechnologies pour la Santé (CPBS), CNRS FRE 3689, Montpellier, France INSERM, CPBS, Montpellier, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Kremer
authors.affiliation: INSERM, U1173, UFR Simone Veil, Université de Versailles Saint Quentin, Saint Quentin en Yvelines, France APHP, Groupe Hospitalo-Universitaire Paris Île-de-France Ouest, Garches et Boulogne-Billancourt, France jean-louis.herrmann@aphp.fr anne.blanc-potard@univ-montp2.fr.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Herrmann
authors.affiliation: Laboratoire de Dynamique des Interactions Membranaires Normales et Pathologiques, Université de Montpellier, Montpellier, France CNRS, UMR5235, Montpellier, France jean-louis.herrmann@aphp.fr anne.blanc-potard@univ-montp2.fr.
authors.forename: Anne-Béatrice
authors.initials: AB
authors.lastname: Blanc-Potard
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics; D001428:Bacterial Vaccines / Q000276:immunology*; D015153:Blotting, Western; D003550:Cystic Fibrosis / Q000150:complications; D004195:Disease Models, Animal; D005260:Female; D008264:Macrophages / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D009161:Mycobacterium / Q000276:immunology*; D009165:Mycobacterium Infections, Nontuberculous / Q000276:immunology* / Q000517:prevention & control; D037521:Virulence Factors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D001428:Bacterial Vaccines; D037521:Virulence Factors