A Bacterial Pathogen Targets a Host Rab-Family GTPase Defense Pathway with a GAP

Cell Host Microbe. 2016 Feb 10;19(2):216-26. doi: 10.1016/j.chom.2016.01.004.

Abstract

Cell-autonomous defense mechanisms are potent strategies that protect individual cells against intracellular pathogens. The Rab-family GTPase Rab32 was previously shown to restrict the intracellular human pathogen Salmonella Typhi, but its potential broader role in antimicrobial defense remains unknown. We show that Rab32 represents a general cell-autonomous, antimicrobial defense that is counteracted by two Salmonella effectors. Mice lacking Rab-32 or its nucleotide exchange factor BLOC-3 are permissive to S. Typhi infection and exhibit increased susceptibility to S. Typhimurium. S. Typhimurium counters this defense pathway by delivering two type III secretion effectors, SopD2, a Rab32 GAP, and GtgE, a specific Rab32 protease. An S. Typhimurium mutant strain lacking these two effectors exhibits markedly reduced virulence, which is fully restored in BLOC-3-deficient mice. These results demonstrate that a cell-autonomous, Rab32-dependent host defense pathway plays a central role in the defense against vacuolar pathogens and describe a mechanism evolved by a bacterial pathogen to counter it.

Keywords: Rab GTPases; Rab32; Salmonella Typhi; Salmonella pathogenesis; bacterial pathogenesis; cell-autonomous defense; innate immunity; lysosome-related organelles; lysosomes; macrophages; membrane traffic; type III secretion; typhoid fever.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism
  • Host-Pathogen Interactions
  • Humans
  • Mice
  • Proteolysis
  • Salmonella Infections / enzymology*
  • Salmonella Infections / genetics
  • Salmonella Infections / microbiology
  • Salmonella typhi / enzymology
  • Salmonella typhi / genetics
  • Salmonella typhi / pathogenicity
  • Salmonella typhi / physiology*
  • Salmonella typhimurium / enzymology
  • Salmonella typhimurium / genetics
  • Salmonella typhimurium / pathogenicity
  • Salmonella typhimurium / physiology*
  • Virulence
  • rab GTP-Binding Proteins / genetics
  • rab GTP-Binding Proteins / metabolism*

Substances

  • Bacterial Proteins
  • Rab32 protein, mouse
  • rab GTP-Binding Proteins