title: Deletion of nuoG from the Vaccine Candidate Mycobacterium bovis BCG ΔureC::hly Improves Protection against Tuberculosis.
abstract: The current tuberculosis (TB) vaccine, Mycobacterium bovis Bacillus Calmette-Guérin (BCG), provides insufficient protection against pulmonary TB. Previously, we generated a listeriolysin-expressing recombinant BCG strain, which to date has successfully completed phase I and phase IIa clinical trials. In an attempt to further improve efficacy, we deleted the antiapoptotic virulence gene nuoG, encoding NADH dehydrogenase 1 subunit G, from BCG ΔureC::hly In vitro, deletion of nuoG unexpectedly led to strongly increased recruitment of the autophagosome marker LC3 to the engulfed vaccine, suggesting that nuoG also affects xenophagic pathways. In mice, BCG ΔureC::hly ΔnuoG vaccination was safer than BCG and improved protection over that of parental BCG ΔureC::hly, significantly reducing TB load in murine lungs, ameliorating pulmonary pathology, and enhancing immune responses. Transcriptome analysis of draining lymph nodes after vaccination with either BCG ΔureC::hly or BCG ΔureC::hly ΔnuoG demonstrated earlier and stronger induction of immune responses than that with BCG SSI and suggested upregulation of inflammasome activation and interferon-induced GTPases. In summary, BCG ΔureC::hly ΔnuoG is a promising next-generation TB vaccine candidate with excellent efficacy and safety.
  
  
  
  Autophagy and apoptosis are fundamental processes allowing cells to degrade their components or kill themselves, respectively. The immune system has adopted these mechanisms to eliminate intracellular pathogens. Residing in host cells, the causative agent of tuberculosis, Mycobacterium tuberculosis, has evolved strategies to set cellular programs of autophagy and apoptosis "on hold." The mycobacterial gene nuoG was found to prevent host cell apoptosis. We have deleted nuoG in the live vaccine candidate BCG ΔureC::hly, which is in phase II clinical development, to leave cellular apoptosis "on go" upon immunization. In preclinical models, this strategy boosted immunity and improved protection from M. tuberculosis infection. Unexpectedly, we obtained compelling evidence that mycobacterial nuoG facilitates inhibition of autophagic pathways, suggesting a new role for this gene in the host-pathogen interplay in tuberculosis.
authors.affiliation: Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany Department of Microbiology and Immunology, National University of Singapore, Yong Loo Lin School of Medicine, Singapore.
authors.forename: Martin
authors.initials: M
authors.lastname: Gengenbacher
authors.affiliation: Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany.
authors.forename: Natalie
authors.initials: N
authors.lastname: Nieuwenhuizen
authors.affiliation: Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany.
authors.forename: Alexis
authors.initials: A
authors.lastname: Vogelzang
authors.affiliation: Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany.
authors.forename: Haipeng
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany.
authors.forename: Peggy
authors.initials: P
authors.lastname: Kaiser
authors.affiliation: Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Schuerer
authors.affiliation: Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany.
authors.forename: Doris
authors.initials: D
authors.lastname: Lazar
authors.affiliation: Max Planck Institute for Infection Biology, Core Facility Genomics/Microarray, Berlin, Germany.
authors.forename: Ina
authors.initials: I
authors.lastname: Wagner
authors.affiliation: Max Planck Institute for Infection Biology, Core Facility Genomics/Microarray, Berlin, Germany.
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Mollenkopf
authors.affiliation: Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany kaufmann@mpiib-berlin.mpg.de.
authors.forename: Stefan H E
authors.initials: SH
authors.lastname: Kaufmann
mesh_terms: D000818:Animals; D001500:BCG Vaccine / Q000008:administration & dosage / Q000009:adverse effects / Q000235:genetics* / Q000276:immunology*; D058491:Bacterial Load; D001426:Bacterial Proteins / Q000235:genetics; D042967:Electron Transport Complex I / Q000235:genetics*; D017353:Gene Deletion; D020869:Gene Expression Profiling; D058847:Inflammasomes / Q000276:immunology; D008168:Lung / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D008198:Lymph Nodes / Q000276:immunology / Q000382:microbiology; D051379:Mice; D009163:Mycobacterium bovis / Q000235:genetics* / Q000276:immunology*; D014397:Tuberculosis, Pulmonary / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control*; D014611:Vaccination
chemical_list: D001500:BCG Vaccine; D001426:Bacterial Proteins; D058847:Inflammasomes; D042967:Electron Transport Complex I