Reactive Persulfides from Salmonella Typhimurium Downregulate Autophagy-Mediated Innate Immunity in Macrophages by Inhibiting Electrophilic Signaling

Cell Chem Biol. 2018 Nov 15;25(11):1403-1413.e4. doi: 10.1016/j.chembiol.2018.08.007. Epub 2018 Sep 6.

Abstract

Reactive persulfides such as cysteine persulfide and glutathione persulfide are produced by bacteria including Salmonella during sulfur metabolism. The biological significance of bacterial reactive persulfides in host-pathogen interactions still warrants investigation. We found that reactive persulfides produced by Salmonella Typhimurium LT2 regulate macrophage autophagy via metabolizing 8-nitroguanosine 3',5'-cyclic monophosphate (8-nitro-cGMP), an electrophilic product of reactive oxygen species and nitric oxide signaling. 8-Nitro-cGMP signaling was required for efficient autophagy-mediated clearance of Salmonella from infected macrophages. In the infected cells, 8-nitro-cGMP caused cGMP adduct formation (S-guanylation) of bacterial surface proteins, which triggered recruitment of autophagy-related proteins p62 and LC3-II to the intracellular bacteria. We also found that Salmonella-produced reactive persulfides downregulated this autophagy by decreasing cellular 8-nitro-cGMP content, thereby inhibiting electrophilic signaling. These data reveal a pathogenic role of bacteria-derived reactive persulfides via suppression of anti-bacterial autophagy.

Keywords: 8-nitroguanosine 3′,5′-cyclic monophosphate; autophagy; electrophilic signaling; host-pathogen interaction; reactive persulfides.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy
  • Cyclic GMP / analogs & derivatives*
  • Cyclic GMP / immunology
  • Host-Pathogen Interactions*
  • Immunity, Innate*
  • Macrophages / immunology*
  • Macrophages / microbiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • RAW 264.7 Cells
  • Reactive Oxygen Species / immunology
  • Salmonella Infections / immunology*
  • Salmonella Infections / microbiology
  • Salmonella typhimurium / immunology*
  • Salmonella typhimurium / physiology
  • Sulfides / immunology*

Substances

  • 8-nitroguanosine 3',5'-cyclic monophosphate
  • Reactive Oxygen Species
  • Sulfides
  • persulfides
  • Cyclic GMP