Intracellular bacteria engage a STING-TBK1-MVB12b pathway to enable paracrine cGAS-STING signalling

Nat Microbiol. 2019 Apr;4(4):701-713. doi: 10.1038/s41564-019-0367-z. Epub 2019 Feb 25.

Abstract

The innate immune system is crucial for eventual control of infections, but may also contribute to pathology. Listeria monocytogenes is an intracellular Gram-positive bacteria and a major cause of food-borne disease. However, important knowledge on the interactions between L. monocytogenes and the immune system is still missing. Here, we report that Listeria DNA is sorted into extracellular vesicles (EVs) in infected cells and delivered to bystander cells to stimulate the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) pathway. This was also observed during infections with Francisella tularensis and Legionella pneumophila. We identify the multivesicular body protein MVB12b as a target for TANK-binding kinase 1 phosphorylation, which is essential for the sorting of DNA into EVs and stimulation of bystander cells. EVs from Listeria-infected cells inhibited T-cell proliferation, and primed T cells for apoptosis. Collectively, we describe a pathway for EV-mediated delivery of foreign DNA to bystander cells, and suggest that intracellular bacteria exploit this pathway to impair antibacterial defence.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • DNA, Bacterial / genetics
  • DNA, Bacterial / metabolism
  • Extracellular Vesicles / metabolism
  • Extracellular Vesicles / microbiology*
  • Host-Pathogen Interactions
  • Humans
  • Listeria monocytogenes / genetics
  • Listeria monocytogenes / physiology*
  • Listeriosis / genetics
  • Listeriosis / metabolism*
  • Listeriosis / microbiology
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Nucleotides, Cyclic
  • Nucleotidyltransferases / genetics
  • Nucleotidyltransferases / metabolism*
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Vesicular Transport Proteins / genetics
  • Vesicular Transport Proteins / metabolism*

Substances

  • DNA, Bacterial
  • MPYS protein, mouse
  • Membrane Proteins
  • Mvb12b protein, mouse
  • Nucleotides, Cyclic
  • Vesicular Transport Proteins
  • cyclic guanosine monophosphate-adenosine monophosphate
  • Tbk1 protein, mouse
  • Protein-Serine-Threonine Kinases
  • Nucleotidyltransferases
  • cGAS protein, mouse