title: The Recombinant BCG ΔureC::hly Vaccine Targets the AIM2 Inflammasome to Induce Autophagy and Inflammation.
abstract: BACKGROUND
  The recombinant BCG ΔureC::hly (rBCG) vaccine candidate induces improved protection against tuberculosis over parental BCG (pBCG) in preclinical studies and has successfully completed a phase 2a clinical trial. However, the mechanisms responsible for the superior vaccine efficacy of rBCG are still incompletely understood. Here, we investigated the underlying biological mechanisms elicited by the rBCG vaccine candidate relevant to its protective efficacy.
  
  
  METHODS
  THP-1 macrophages were infected with pBCG or rBCG, and inflammasome activation and autophagy were evaluated. In addition, mice were vaccinated with pBCG or rBCG, and gene expression in the draining lymph nodes was analyzed by microarray at day 1 after vaccination.
  
  
  RESULTS
  BCG-derived DNA was detected in the cytosol of rBCG-infected macrophages. rBCG infection was associated with enhanced absent in melanoma 2 (AIM2) inflammasome activation, increased activation of caspases and production of interleukin (IL)-1β and IL-18, as well as induction of AIM2-dependent and stimulator of interferon genes (STING)-dependent autophagy. Similarly, mice vaccinated with rBCG showed early increased expression of Il-1β, Il-18, and Tmem173 (transmembrane protein 173; also known as STING).
  
  
  CONCLUSIONS
  rBCG stimulates AIM2 inflammasome activation and autophagy, suggesting that these cell-autonomous functions should be exploited for improved vaccine design.
authors.affiliation: Department of Immunology.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Saiga
authors.affiliation: Department of Immunology.
authors.forename: Natalie
authors.initials: N
authors.lastname: Nieuwenhuizen
authors.affiliation: Department of Immunology.
authors.forename: Martin
authors.initials: M
authors.lastname: Gengenbacher
authors.affiliation: Department of Immunology.
authors.forename: Anne-Britta
authors.initials: AB
authors.lastname: Koehler
authors.affiliation: Department of Immunology.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Schuerer
authors.affiliation: Department of Immunology.
authors.forename: Pedro
authors.initials: P
authors.lastname: Moura-Alves
authors.affiliation: Core Facility Microarray, Max Planck Institute for Infection Biology, Berlin, Germany.
authors.forename: Ina
authors.initials: I
authors.lastname: Wagner
authors.affiliation: Core Facility Microarray, Max Planck Institute for Infection Biology, Berlin, Germany.
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Mollenkopf
authors.affiliation: Department of Immunology.
authors.forename: Anca
authors.initials: A
authors.lastname: Dorhoi
authors.affiliation: Department of Immunology.
authors.forename: Stefan H E
authors.initials: SH
authors.lastname: Kaufmann
mesh_terms: D000818:Animals; D001343:Autophagy / Q000276:immunology*; D001500:BCG Vaccine / Q000276:immunology*; D002460:Cell Line; D005260:Female; D006801:Humans; D058847:Inflammasomes / Q000276:immunology*; D007249:Inflammation; D020382:Interleukin-18 / Q000276:immunology; D053583:Interleukin-1beta / Q000276:immunology; D008198:Lymph Nodes / Q000737:chemistry / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D014376:Tuberculosis / Q000276:immunology*; D014614:Vaccines, Synthetic / Q000276:immunology*
chemical_list: D001500:BCG Vaccine; D058847:Inflammasomes; D020382:Interleukin-18; D053583:Interleukin-1beta; D014614:Vaccines, Synthetic
keywords: autophagy; inflammasome; innate immunity; macrophages; recombinant BCG ΔureC::hly; tuberculosis; vaccination