title: Listeria monocytogenes mutants defective in gallbladder replication represent safety-enhanced vaccine delivery platforms.
abstract: The Gram positive intracellular pathogen Listeria monocytogenes represents a promising vaccine or therapeutic DNA delivery vector that has been successfully administered to humans in clinical trials. However in generating Listeria mutants with therapeutic potential it is important to balance safety attenuation with efficacy. Here we show that L. monocytogenes mutants with a reduced capacity for murine gallbladder replication are capable of stimulating T cell responses in mice and protecting vaccinated animals from secondary challenge. Mutation of L. monocytogenes genes lmo2566 or lmo0598 resulted in significant attenuation in the murine model yet mutants retained a capacity for intracellular growth and stimulation of T cell responses against key Listeria epitopes (LLO91-99and P60217-225). Importantly the mutants showed a reduced capacity for growth in the gallbladders of vaccinated mice as well as significantly reduced faecal shedding indicating that this approach generates live Listeria-based vector delivery systems with a reduced capacity for the spread of live genetically modified microorganisms into the natural environment.
authors.affiliation: a APC Microbiome Institute, University College Cork , Cork , Ireland.|b School of Microbiology, University College Cork , Cork , Ireland.
authors.forename: Georgina C
authors.initials: GC
authors.lastname: Dowd
authors.affiliation: a APC Microbiome Institute, University College Cork , Cork , Ireland.|b School of Microbiology, University College Cork , Cork , Ireland.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Bahey-El-Din
authors.affiliation: a APC Microbiome Institute, University College Cork , Cork , Ireland.|b School of Microbiology, University College Cork , Cork , Ireland.
authors.forename: Pat G
authors.initials: PG
authors.lastname: Casey
authors.affiliation: a APC Microbiome Institute, University College Cork , Cork , Ireland.|c School of Biochemistry & Cell Biology, University College Cork , Cork , Ireland.
authors.forename: Susan A
authors.initials: SA
authors.lastname: Joyce
authors.affiliation: a APC Microbiome Institute, University College Cork , Cork , Ireland.|b School of Microbiology, University College Cork , Cork , Ireland.
authors.forename: Colin
authors.initials: C
authors.lastname: Hill
authors.affiliation: a APC Microbiome Institute, University College Cork , Cork , Ireland.|b School of Microbiology, University College Cork , Cork , Ireland.|d School of Pharmacy, University College Cork , Cork , Ireland.
authors.forename: Cormac G M
authors.initials: CG
authors.lastname: Gahan
mesh_terms: D000818:Animals; D001428:Bacterial Vaccines / Q000008:administration & dosage / Q000009:adverse effects* / Q000276:immunology*; D004337:Drug Carriers; D005704:Gallbladder / Q000382:microbiology*; D008089:Listeria monocytogenes / Q000254:growth & development* / Q000276:immunology / Q000472:pathogenicity*; D008088:Listeriosis / Q000517:prevention & control*; D008807:Mice, Inbred BALB C; D055502:Secondary Prevention; D013601:T-Lymphocytes / Q000276:immunology; D037521:Virulence Factors / Q000172:deficiency*
chemical_list: D001428:Bacterial Vaccines; D004337:Drug Carriers; D037521:Virulence Factors
keywords: GMM; GMO; Listeria vaccine; biological containment; vaccine safety