A "suicide" BCG strain provides enhanced immunogenicity and robust protection against Mycobacterium tuberculosis in macaques.

Autor: Smith AA; Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh PA.; The Center for Vaccine Research, University of Pittsburgh School of Medicine, Pittsburgh PA., Su H; Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY 10021, USA.; Present address: Center for Veterinary Science, Zhejiang University, Hangzhou, China., Wallach J; Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY 10021, USA., Liu Y; Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY 10021, USA., Maiello P; Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh PA.; The Center for Vaccine Research, University of Pittsburgh School of Medicine, Pittsburgh PA., Borish HJ; Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh PA.; The Center for Vaccine Research, University of Pittsburgh School of Medicine, Pittsburgh PA., Winchell C; Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh PA., Simonson AW; Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh PA.; The Center for Vaccine Research, University of Pittsburgh School of Medicine, Pittsburgh PA., Lin PL; The Center for Vaccine Research, University of Pittsburgh School of Medicine, Pittsburgh PA.; Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA., Rodgers M; Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh PA.; The Center for Vaccine Research, University of Pittsburgh School of Medicine, Pittsburgh PA., Fillmore D; Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh PA.; The Center for Vaccine Research, University of Pittsburgh School of Medicine, Pittsburgh PA., Sakal J; Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh PA.; The Center for Vaccine Research, University of Pittsburgh School of Medicine, Pittsburgh PA., Lin K; Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY 10021, USA., Vinette V; Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY 10021, USA., Schnappinger D; Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY 10021, USA., Ehrt S; Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY 10021, USA., Flynn JL; Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh PA.; The Center for Vaccine Research, University of Pittsburgh School of Medicine, Pittsburgh PA.
Jazyk: angličtina
Zdroj: BioRxiv : the preprint server for biology [bioRxiv] 2024 Sep 05. Date of Electronic Publication: 2024 Sep 05.
DOI: 10.1101/2023.11.22.568105
Abstrakt: Intravenous (IV) BCG delivery provides robust protection against Mycobacterium tuberculosis (Mtb) in macaques but poses safety challenges. Here, we constructed two BCG strains (BCG-TetON-DL and BCG-TetOFF-DL) in which tetracyclines regulate two phage lysin operons. Once the lysins are expressed, these strains are killed in immunocompetent and immunocompromised mice yet induced similar immune responses and provided similar protection against Mtb challenge as wild type BCG. Lysin induction resulted in release of intracellular BCG antigens and enhanced cytokine production by macrophages. In macaques, cessation of doxycycline administration resulted in rapid elimination of BCG-TetOFF-DL. However, IV BCG-TetOFF-DL induced increased pulmonary CD4 T cell responses compared to WT BCG and provided robust protection against Mtb challenge, with sterilizing immunity in 6 of 8 macaques, compared to 2 of 8 macaques immunized with WT BCG. Thus, a "suicide" BCG strain provides an additional measure of safety when delivered intravenously and robust protection against Mtb infection.
Databáze: MEDLINE