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

Stefania Spano, Xiang Gao, Sebastian Hanneman, Maria Lara-Tejero, Jorge E. Galan

Research output: Contribution to journalArticle

42 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)216-226
Number of pages11
JournalCell Host & Microbe
Volume19
Issue number2
DOIs
Publication statusPublished - 10 Feb 2016

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rab GTP-Binding Proteins
Salmonella typhi
Salmonella Infections
Salmonella
Virulence
Peptide Hydrolases
Nucleotides

Keywords

  • bacterial pathogenesis
  • cell-autonomous defense
  • type III secretion
  • RAB GTpases
  • Rab32
  • membrane traffic
  • macrophages
  • innate immunity
  • lysosomes
  • lysosome-related organelles
  • salmonella pathogenesis
  • Salmonella typhi
  • typhoid fever

Cite this

Spano, S., Gao, X., Hanneman, S., Lara-Tejero, M., & Galan, J. E. (2016). A Bacterial Pathogen Targets a Host Rab-Family GTPase Defense Pathway with a GAP. Cell Host & Microbe, 19(2), 216-226. https://doi.org/10.1016/j.chom.2016.01.004

A Bacterial Pathogen Targets a Host Rab-Family GTPase Defense Pathway with a GAP. / Spano, Stefania; Gao, Xiang; Hanneman, Sebastian ; Lara-Tejero, Maria; Galan, Jorge E.

In: Cell Host & Microbe, Vol. 19, No. 2, 10.02.2016, p. 216-226.

Research output: Contribution to journalArticle

Spano, S, Gao, X, Hanneman, S, Lara-Tejero, M & Galan, JE 2016, 'A Bacterial Pathogen Targets a Host Rab-Family GTPase Defense Pathway with a GAP', Cell Host & Microbe, vol. 19, no. 2, pp. 216-226. https://doi.org/10.1016/j.chom.2016.01.004
Spano, Stefania ; Gao, Xiang ; Hanneman, Sebastian ; Lara-Tejero, Maria ; Galan, Jorge E. / A Bacterial Pathogen Targets a Host Rab-Family GTPase Defense Pathway with a GAP. In: Cell Host & Microbe. 2016 ; Vol. 19, No. 2. pp. 216-226.
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AB - 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.

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